Professor of Otolaryngology - Head and Neck Surgery and, by courtesy, of Pediatrics and of Neurosurgery

Otolaryngology (Head and Neck Surgery)

Bio

Bio

Otolaryngology ? Head and Neck Surgery is a surgical specialty and I consider the care of the patient in front of me to be of paramount importance. My ultimate goal is to improve human health not only by caring for my patients expertly, but also by advancing our scientific knowledge base so that all physicians can treat disease more effectively. I am following a clinician-scientist pathway and have found basic and translational research to be synergistic with my clinical activities. In particular, treating patients helps me to develop a meaningful research agenda. I believe that developing and maintaining a university-based medical practice requires a tertiary level of care based upon providing clinical excellence, incorporating the latest research, and delivering patient-centered service. Personally, I have developed a nationwide referral practice in the subspecialty care of patients with diseases of the ear and skull base. My adult practice focuses on the management of skull base tumors such as vestibular schwannoma (acoustic neuroma) and meningioma. I work closely with the Departments of Neurosurgery, Radiation Oncology, and Neuroradiology as part of the skull base team. My pediatric practice focuses on the evaluation and management of children with hearing loss, in particular, I am the Director of the Stanford Children's Hearing Center and its pediatric cochlear implant team.

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Research & Scholarship

Current Research and Scholarly Interests

The Oghalai lab has two major thrusts. Our basic science/translational research efforts are designed to better understand the mechanisms of hearing loss and our clinical research approaches are targeted to directly and rapidly improve the care of patients with hearing loss.

Translational Research

A common clinical scenario is that a child is initially identified with a partial hearing loss, which then progresses to profound hearing loss over a period of months to years. Genetic defects are responsible for over half of these cases, however the specific mechanisms of how many of these mutations cause progressive sensorineural hearing loss is unclear. Right now, all we typically can tell a patient with hearing loss is that we know they have hearing loss, and that it is because of a problem in the cochlea. There are no more detailed tests available.

Because of the difficulty in performing auditory research in humans, we study normal and transgenic mice that have hearing loss. We strive to perform comprehensive evaluation of the pathophysiology that creates the hearing loss. For example, cochlear function is monitored with measurements of the compound action potential, the auditory evoked brainstem response, distortion product otoacoustic emissions, the cochlear microphonic, and the olivocochlear reflex. Basilar membrane motion is measured using laser doppler vibrometry. Histological study of the inner ear is performed using immunohistochemistry. We also use the patch-clamp technique with to study hair cell and spiral ganglion cell physiology. Recently, we have begun using fluorescent-activated cell sorting (FACS) to isolate outer hair cells from the adult cochlea after noise or blast exposure to study the regulation of genes after cellular injury.

We are, however, working to develop techniques that will allow us to perform research in humans. For example, we are in the process of developing novel optical techniques for in vivo imaging using optical coherence tomography (OCT). The level of detail within the cochlea that we can now image is roughly two orders of magnitude better than what is currently available with the latest MRI or CT techniques. Our goal is to be able to identify why any given patient that comes to clinic has hearing loss, and use this information to guide management using regenerative strategies that are in active development.

Clinical Research:

Our clinical research is focused on improving what we are currently doing to help children with deafness. Cochlear implants (CI) are the most common treatment for deafness. While many factors influence the ability of a deaf child who is hearing through a CI to develop speech and language skills, an important factor is to properly program the CI. However, implementing the optimal CI program is a challenging, individualized, and iterative process with variable success.NIRS Headset

One difficulty in CI programming is obtaining behavioral measurements from the young children in which CIs are usually implanted. Therefore, we are developing the technique of near-infrared spectroscopy (NIRS) to functionally image activity within the auditory cortex of children hearing through a cochlear implant.

As well, we are running a multi-site, prospective randomized clinical trial of deaf children with special needs. The goal of the study is to determine the best treatment options for children that require such complex and individualized care. This trial is actively enrolling participants at Lucile Packard Children’s Hospital in Palo Alto, CA and at Texas Children’s Hospital in Houston, TX.

Clinical Trials

Outcomes In Children With Developmental Delay And DeafnessNot Recruiting

Children with special needs require complex, individualized therapy to maximize their
long-term quality of life. One subset of children with special needs includes those with
both developmental delays and deafness. Currently, there is little compelling evidence
supporting the idea that cochlear implantation provides benefit to children that don't have
the cognitive potential to develop normal speech and language.
We will perform a prospective, randomized clinical trial to answer the question of which
intervention provides more benefit to this population of children using validated,
norm-referenced tests.
Our long-term goal is to develop guidelines that may help when selecting a treatment for
hearing loss in a child with developmental delays.
This proposal is significant because children with special needs are deserving of evidence
upon which to base treatment decision-making, but remain under-represented in the medical
literature and are often not studied. This research is designed to meet the criteria for the
National Institutes of Health road map because it will generate this type of objective
evidence that can directly improve patient care.

Stanford is currently not accepting patients for this trial.For more information, please contact John Oghalai, MD, 650-725-6500.

Abstract

Neuroplastin (Nptn) is a member of the Ig superfamily and is expressed in two isoforms, Np55 and Np65. Np65 regulates synaptic transmission but the function of Np55 is unknown. In an N-ethyl-N-nitrosaurea mutagenesis screen, we have now generated a mouse line with an Nptn mutation that causes deafness. We show that Np55 is expressed in stereocilia of outer hair cells (OHCs) but not inner hair cells and affects interactions of stereocilia with the tectorial membrane. In vivo vibrometry demonstrates that cochlear amplification is absent in Nptn mutant mice, which is consistent with the failure of OHC stereocilia to maintain stable interactions with the tectorial membrane. Hair bundles show morphological defects as the mutant mice age and while mechanotransduction currents can be evoked in early postnatal hair cells, cochlea microphonics recordings indicate that mechanontransduction is affected as the mutant mice age. We thus conclude that differential splicing leads to functional diversification of Nptn, where Np55 is essential for OHC function, while Np65 is implicated in the regulation of synaptic function.Amplification of input sound signals, which is needed for the auditory sense organ to detect sounds over a wide intensity range, depends on mechanical coupling of outer hair cells to the tectorial membrane. The current study shows that neuroplastin, a member of the Ig superfamily, which has previously been linked to the regulation of synaptic plasticity, is critical to maintain a stable mechanical link of outer hair cells with the tectorial membrane. In vivo recordings demonstrate that neuroplastin is essential for sound amplification and that mutation in neuroplastin leads to auditory impairment in mice.

Abstract

The exquisite sensitivity and frequency discrimination of mammalian hearing underlie the ability to understand complex speech in noise. This requires force generation by cochlear outer hair cells (OHCs) to amplify the basilar membrane traveling wave; however, it is unclear how amplification is achieved with sharp frequency tuning. Here we investigated the origin of tuning by measuring sound-induced 2-D vibrations within the mouse organ of Corti in vivo Our goal was to determine the transfer function relating the radial shear between the structures that deflect the OHC bundle, the tectorial membrane and reticular lamina, to the transverse motion of the basilar membrane. We found that, after normalizing their responses to the vibration of the basilar membrane, the radial vibrations of the tectorial membrane and reticular lamina were tuned. The radial tuning peaked at a higher frequency than transverse basilar membrane tuning in the passive, postmortem condition. The radial tuning was similar in dead mice, indicating that this reflected passive, not active, mechanics. These findings were exaggerated in Tecta(C1509G/C1509G) mice, where the tectorial membrane is detached from OHC stereocilia, arguing that the tuning of radial vibrations within the hair cell epithelium is distinct from tectorial membrane tuning. Together, these results reveal a passive, frequency-dependent contribution to cochlear filtering that is independent of basilar membrane filtering. These data argue that passive mechanics within the organ of Corti sharpen frequency selectivity by defining which OHCs enhance the vibration of the basilar membrane, thereby tuning the gain of cochlear amplification.Outer hair cells amplify the traveling wave within the mammalian cochlea. The resultant gain and frequency sharpening are necessary for speech discrimination, particularly in the presence of background noise. Here we measured the 2-D motion of the organ of Corti in mice and found that the structures that stimulate the outer hair cell stereocilia, the tectorial membrane and reticular lamina, were sharply tuned in the radial direction. Radial tuning was similar in dead mice and in mice lacking a tectorial membrane. This suggests that radial tuning comes from passive mechanics within the hair cell epithelium, and that these mechanics, at least in part, may tune the gain of cochlear amplification.

Abstract

Functional neuroimaging can provide insight into the neurobiological factors that contribute to the variations in individual hearing outcomes following cochlear implantation. To date, measuring neural activity within the auditory cortex of cochlear implant (CI) recipients has been challenging, primarily because the use of traditional neuroimaging techniques is limited in people with CIs. Functional near-infrared spectroscopy (fNIRS) is an emerging technology that offers benefits in this population because it is non-invasive, compatible with CI devices, and not subject to electrical artifacts. However, there are important considerations to be made when using fNIRS to maximize the signal to noise ratio and to best identify meaningful cortical responses. This review considers these issues, the current data, and future directions for using fNIRS as a clinical application in individuals with CIs.

Abstract

Although hyperbilirubinemia is extremely common among neonates and is usually mild and transient, it sometimes leads to bilirubin-induced neurologic damage (BIND). The auditory pathway is highly sensitive to the effects of elevated total serum/plasma bilirubin (TB) levels, with damage manifesting clinically as auditory neuropathy spectrum disorder. Compared to full-term neonates, preterm neonates are more susceptible to BIND and suffer adverse effects at lower TB levels with worse long-term outcomes. Furthermore, although standardized guidelines for management of hyperbilirubinemia exist for term and late preterm neonates, similar guidelines for neonates less than 35 weeks gestational age are limited.

Abstract

Cochlear implants are a standard therapy for deafness, yet the ability of implanted patients to understand speech varies widely. To better understand this variability in outcomes, the authors used functional near-infrared spectroscopy to image activity within regions of the auditory cortex and compare the results to behavioral measures of speech perception.The authors studied 32 deaf adults hearing through cochlear implants and 35 normal-hearing controls. The authors used functional near-infrared spectroscopy to measure responses within the lateral temporal lobe and the superior temporal gyrus to speech stimuli of varying intelligibility. The speech stimuli included normal speech, channelized speech (vocoded into 20 frequency bands), and scrambled speech (the 20 frequency bands were shuffled in random order). The authors also used environmental sounds as a control stimulus. Behavioral measures consisted of the speech reception threshold, consonant-nucleus-consonant words, and AzBio sentence tests measured in quiet.Both control and implanted participants with good speech perception exhibited greater cortical activations to natural speech than to unintelligible speech. In contrast, implanted participants with poor speech perception had large, indistinguishable cortical activations to all stimuli. The ratio of cortical activation to normal speech to that of scrambled speech directly correlated with the consonant-nucleus-consonant words and AzBio sentences scores. This pattern of cortical activation was not correlated with auditory threshold, age, side of implantation, or time after implantation. Turning off the implant reduced the cortical activations in all implanted participants.Together, these data indicate that the responses the authors measured within the lateral temporal lobe and the superior temporal gyrus correlate with behavioral measures of speech perception, demonstrating a neural basis for the variability in speech understanding outcomes after cochlear implantation.

Abstract

Swept-laser sources offer a number of advantages for Phase-sensitive Optical Coherence Tomography (PhOCT). However, inter- and intra-sweep variability leads to calibration errors that adversely affect phase sensitivity. While there are several approaches to overcoming this problem, our preferred method is to simply calibrate every sweep of the laser. This approach offers high accuracy and phase stability at the expense of a substantial processing burden. In this approach, the Hilbert phase of the interferogram from a reference interferometer provides the instantaneous wavenumber of the laser, but is computationally expensive. Fortunately, the Hilbert transform may be approximated by a Finite Impulse-Response (FIR) filter. Here we explore the use of several FIR filter based Hilbert transforms for calibration, explicitly considering the impact of filter choice on phase sensitivity and OCT image quality. Our results indicate that the complex FIR filter approach is the most robust and accurate among those considered. It provides similar image quality and slightly better phase sensitivity than the traditional FFT-IFFT based Hilbert transform while consuming fewer resources in an FPGA implementation. We also explored utilizing the Hilbert magnitude of the reference interferogram to calculate an ideal window function for spectral amplitude calibration. The ideal window function is designed to carefully control sidelobes on the axial point spread function. We found that after a simple chromatic correction, calculating the window function using the complex FIR filter and the reference interferometer gave similar results to window functions calculated using a mirror sample and the FFT-IFFT Hilbert transform. Hence, the complex FIR filter can enable accurate and high-speed calibration of the magnitude and phase of spectral interferograms.

Abstract

The measurement of mechanical vibrations within the living cochlea is critical to understanding the first nonlinear steps in auditory processing, hair cell stimulation, and cochlear amplification. However, it has proven to be a challenging endeavor. This chapter describes how optical coherence tomography (OCT) can be used to measure vibrations within the tissues of the organ of Corti. These experimental measurements can be performed within the unopened cochlea of living mice routinely and reliably.

Abstract

Prestin is a membrane protein necessary for outer hair cell (OHC) electromotility and normal hearing. Its regulatory mechanisms are unknown. Several mouse models of hearing loss demonstrate increased prestin, inspiring us to investigate how hearing loss might feedback onto OHCs. To test whether centrally mediated feedback regulates prestin, we developed a novel model of inner hair cell loss. Injection of diphtheria toxin (DT) into adult CBA mice produced significant loss of inner hair cells without affecting OHCs. Thus, DT-injected mice were deaf because they had no afferent auditory input despite OHCs continuing to receive normal auditory mechanical stimulation and having normal function. Patch-clamp experiments demonstrated no change in OHC prestin, indicating that loss of information transfer centrally did not alter prestin expression. To test whether local mechanical feedback regulates prestin, we used Tecta(C1509G) mice, where the tectorial membrane is malformed and only some OHCs are stimulated. OHCs connected to the tectorial membrane had normal prestin levels, whereas OHCs not connected to the tectorial membrane had elevated prestin levels, supporting an activity-dependent model. To test whether the endocochlear potential was necessary for prestin regulation, we studied Tecta(C1509G) mice at different developmental ages. OHCs not connected to the tectorial membrane had lower than normal prestin levels before the onset of the endocochlear potential and higher than normal prestin levels after the onset of the endocochlear potential. Taken together, these data indicate that OHC prestin levels are regulated through local feedback that requires mechanoelectrical transduction currents. This adaptation may serve to compensate for variations in the local mechanical environment.

Abstract

We demonstrate a miniature, tunable, minimally invasive endoscope for diagnosis of the auditory system. The probe is designed to sharply image anatomical details of the middle ear without the need for physically adjusting the position of the distal end of the endoscope. This is achieved through the addition of an electrowetted, tunable, electronically-controlled lens to the optical train. Morphological imaging is enabled by scanning light emanating from an optical coherence tomography system. System performance was demonstrated by imaging part of the ossicular chain and wall of the middle ear cavity of a normal mouse. During the experiment, we electronically moved the plane of best focus from the incudo-stapedial joint to the stapedial artery. Repositioning the object plane allowed us to image anatomical details of the middle ear beyond the depth of field of a static optical system. We also demonstrated for the first time to our best knowledge, that an optical system with an electrowetted, tunable lens may be successfully employed to measure sound-induced vibrations within the auditory system by measuring the vibratory amplitude of the tympanic membrane in a normal mouse in response to pure tone stimuli.

Abstract

Sound is encoded within the auditory portion of the inner ear, the cochlea, after propagating down its length as a traveling wave. For over half a century, vibratory measurements to study cochlear traveling waves have been made using invasive approaches such as laser Doppler vibrometry. Although these studies have provided critical information regarding the nonlinear processes within the living cochlea that increase the amplitude of vibration and sharpen frequency tuning, the data have typically been limited to point measurements of basilar membrane vibration. In addition, opening the cochlea may alter its function and affect the findings. Here we describe volumetric optical coherence tomography vibrometry, a technique that overcomes these limitations by providing depth-resolved displacement measurements at 200 kHz inside a 3D volume of tissue with picometer sensitivity. We studied the mouse cochlea by imaging noninvasively through the surrounding bone to measure sound-induced vibrations of the sensory structures in vivo, and report, to our knowledge, the first measures of tectorial membrane vibration within the unopened cochlea. We found that the tectorial membrane sustains traveling wave propagation. Compared with basilar membrane traveling waves, tectorial membrane traveling waves have larger dynamic ranges, sharper frequency tuning, and apically shifted positions of peak vibration. These findings explain discrepancies between previously published basilar membrane vibration and auditory nerve single unit data. Because the tectorial membrane directly overlies the inner hair cell stereociliary bundles, these data provide the most accurate characterization of the stimulus shaping the afferent auditory response available to date.

Abstract

Hyperbilirubinemia occurs commonly in neonates and is usually mild and transient, with no long-lasting sequelae. However, bilirubin-induced neurologic damage may occur in some infants. The auditory pathway is the most sensitive part of the central nervous system to bilirubin-induced toxicity, and permanent sequelae may result from only moderately elevated total serum/plasma bilirubin levels. The damage to the auditory system occurs primarily within the brainstem and cranial nerve VIII, and manifests clinically as auditory neuropathy spectrum disorder.

Abstract

Stage IVb juvenile nasopharyngeal angiofibromas (JNAs) are frequently regarded as unresectable because of their intracranial extension and cavernous sinus invasion. Although radiation has been described to control these tumors, it can leave the adolescent with long-lasting sequelae. Herein, we describe an alternative treatment strategy based on a combined subtemporal-transfacial surgical approach that permits the successful management of advanced stage JNAs by divorcing the intracranial vascular supply to these massive lesions.Four male patients were identified with Andrew's Stage IVB JNAs.All patients were treated by surgical resection using a combined subtemporal-transfacial surgical approach.Parameters assessed included tumor extent, number and types of surgical procedures, extent of resections, complications, and recurrence rate.Near-total tumor resections were achieved in all patients. No cerebrospinal fluid leak or cranial neuropathies were noted. All but one patient had local recurrences, and these could be managed with repetitive endoscopic debridement. No patient required adjuvant radiation treatment to control advanced disease.With the use of modern skull base surgical techniques, coordinated interdisciplinary care, and safe, near-total removal of the tumor mass, adolescent males with advanced JNAs may be spared the long-term morbidities associated with using radiation to treat these benign but aggressive lesions.

Abstract

Patients with large vestibular schwannomas are at high risk of poor facial nerve (cranial nerve VII [CNVII]) function after surgery. Subtotal resection potentially offers better outcome, but may lead to higher tumor regrowth.To assess long-term CNVII function and tumor regrowth in patients with large vestibular schwannomas.Prospective multicenter nonrandomized cohort study of patients with vestibular schwannoma ?2.5 cm who received gross total resection, near total resection, or subtotal resection. Patients received radiation if tumor remnant showed signs of regrowth.Seventy-three patients had adequate follow-up with mean tumor diameter of 3.33 cm. Twelve received gross total resection, 22 near total resection, and 39 subtotal resection. Fourteen (21%) remnant tumors continued to grow, of which 11 received radiation, 1 had repeat surgery, and 2 no treatment. Four of the postradiation remnants (36%) required surgical salvage. Tumor regrowth was related to non-cystic nature, larger residual tumor, and subtotal resection. Regrowth was 3 times as likely with subtotal resection compared to gross total resection and near total resection. Good CNVII function was achieved in 67% immediately and 81% at 1-year. Better immediate nerve function was associated with smaller preoperative tumor size and percentage of tumor left behind on magnetic resonance image. Degree of resection defined by surgeon and preoperative tumor size showed weak trend toward better late CNVII function.Likelihood of tumor regrowth was 3 times higher in subtotal resection compared to gross total resection and near total resection groups. Rate of radiation control of growing remnants was suboptimal. Better immediate but not late CNVII outcome was associated with smaller tumors and larger tumor remnants.CNVII, cranial nerve VIIGTR, gross total resectionHB, House-BrackmannMRI, magnetic resonance imageNTR, near total resectionSTR, subtotal resection.

Abstract

Sensorineural hearing loss is most commonly caused by the death of hair cells in the organ of Corti, and once lost, mammalian hair cells do not regenerate. In contrast, other vertebrates such as birds can regenerate hair cells by stimulating division and differentiation of neighboring supporting cells. We currently know little of the genetic networks which become active in supporting cells when hair cells die and that are activated in experimental models of hair cell regeneration. Several studies have shown that neonatal mammalian cochlear supporting cells are able to trans-differentiate into hair cells when cultured in conditions in which the Notch signaling pathway is blocked. We now show that the ability of cochlear supporting cells to trans-differentiate declines precipitously after birth, such that supporting cells from six-day-old mouse cochlea are entirely unresponsive to a blockade of the Notch pathway. We show that this trend is seen regardless of whether the Notch pathway is blocked with gamma secretase inhibitors, or by antibodies against the Notch1 receptor, suggesting that the action of gamma secretase inhibitors on neonatal supporting cells is likely to be by inhibiting Notch receptor cleavage. The loss of responsiveness to inhibition of the Notch pathway in the first postnatal week is due in part to a down-regulation of Notch receptors and ligands, and we show that this down-regulation persists in the adult animal, even under conditions of noise damage. Our data suggest that the Notch pathway is used to establish the repeating pattern of hair cells and supporting cells in the organ of Corti, but is not required to maintain this cellular mosaic once the production of hair cells and supporting cells is completed. Our results have implications for the proposed used of Notch pathway inhibitors in hearing restoration therapies.

Abstract

Aetiological assessment of 71 probands whose clinical presentation suggested a genetic syndrome or auditory neuropathy.Sanger sequencing was performed on DNA isolated from peripheral blood or lymphoblastoid cell lines. Genes were selected for sequencing based on each patient's clinical presentation and suspected diagnosis. Observed DNA sequence variations were assessed for pathogenicity by review of the scientific literature, and mutation and polymorphism databases, through the use of in silico tools including sorting intolerant from tolerant (SIFT) and polymorphism phenotyping (PolyPhen), and according to the recommendations of the American College of Medical Genetics and Genomics for the interpretation of DNA sequence variations. Novel DNA sequence variations were sought in controls.DNA sequencing of the coding and near-coding regions of genes relevant to each patient's clinical presentation revealed 37 sequence variations of known or uncertain pathogenicity in 9 genes from 25 patients. 14 novel sequence variations were discovered. Assessment of phenotypes revealed notable findings in 9 patients.DNA sequencing in patients whose clinical presentation suggested a genetic syndrome or auditory neuropathy provided opportunities for aetiological assessment and more precise genetic counselling of patients and families. The failure to identify a genetic aetiology in many patients in this study highlights the extreme heterogeneity of genetic hearing loss, the incompleteness of current knowledge of aetiologies of hearing loss, and the limitations of conventional DNA sequencing strategies that evaluate only coding and near-coding segments of genes.

Abstract

The tonotopic map of the mammalian cochlea is commonly thought to be determined by the passive mechanical properties of the basilar membrane. The other tissues and cells that make up the organ of Corti also have passive mechanical properties; however, their roles are less well understood. In addition, active forces produced by outer hair cells (OHCs) enhance the vibration of the basilar membrane, termed cochlear amplification. Here, we studied how these biomechanical components interact using optical coherence tomography, which permits vibratory measurements within tissue. We measured not only classical basilar membrane tuning curves, but also vibratory responses from the rest of the organ of Corti within the mouse cochlear apex in vivo. As expected, basilar membrane tuning was sharp in live mice and broad in dead mice. Interestingly, the vibratory response of the region lateral to the OHCs, the "lateral compartment," demonstrated frequency-dependent phase differences relative to the basilar membrane. This was sharply tuned in both live and dead mice. We then measured basilar membrane and lateral compartment vibration in transgenic mice with targeted alterations in cochlear mechanics. Prestin(499/499), Prestin(-/-), and Tecta(C1509G/C1509G) mice demonstrated no cochlear amplification but maintained the lateral compartment phase difference. In contrast, Sfswap(Tg/Tg) mice maintained cochlear amplification but did not demonstrate the lateral compartment phase difference. These data indicate that the organ of Corti has complex micromechanical vibratory characteristics, with passive, yet sharply tuned, vibratory characteristics associated with the supporting cells. These characteristics may tune OHC force generation to produce the sharp frequency selectivity of mammalian hearing.

Abstract

The primary goal of most cochlear implant procedures is to improve a patient's ability to discriminate speech. To accomplish this, cochlear implants are programmed so as to maximize speech understanding. However, programming a cochlear implant can be an iterative, labor-intensive process that takes place over months. In this study, we sought to determine whether functional near-infrared spectroscopy (fNIRS), a non-invasive neuroimaging method which is safe to use repeatedly and for extended periods of time, can provide an objective measure of whether a subject is hearing normal speech or distorted speech. We used a 140 channel fNIRS system to measure activation within the auditory cortex in 19 normal hearing subjects while they listed to speech with different levels of intelligibility. Custom software was developed to analyze the data and compute topographic maps from the measured changes in oxyhemoglobin and deoxyhemoglobin concentration. Normal speech reliably evoked the strongest responses within the auditory cortex. Distorted speech produced less region-specific cortical activation. Environmental sounds were used as a control, and they produced the least cortical activation. These data collected using fNIRS are consistent with the fMRI literature and thus demonstrate the feasibility of using this technique to objectively detect differences in cortical responses to speech of different intelligibility.

Nonverbal Cognitive Development in Children With Cochlear Implants: Relationship Between the Mullen Scales of Early Learning and Later Performance on the Leiter International Performance Scales-RevisedASSESSMENTCaudle, S. E., Katzenstein, J. M., Oghalai, J. S., Lin, J., Caudle, D. D.2014; 21 (1): 119-128

Abstract

Methodologically, longitudinal assessment of cognitive development in young children has proven difficult because few measures span infancy through school age. This matter is further complicated when the child presents with a sensory deficit such as hearing loss. Few measures are validated in this population, and children who are evaluated for cochlear implantation are often reevaluated annually. The authors sought to evaluate the predictive validity of subscales of the Mullen Scales of Early Learning (MSEL) on Leiter International Performance Scales-Revised (LIPS-R) Full-Scale IQ scores. To further elucidate the relationship of these two measures, comparisons were also made with the Vineland Adaptive Behavior Scale-Second Edition (VABS), which provides a measure of adaptive functioning across the life span. Participants included 35 children (14 female, 21 male) who were evaluated both as part of the precandidacy process for cochlear implantation using the MSEL and VABS and following implantation with the LIPS-R and VABS. Hierarchical linear regression revealed that the MSEL Visual Reception subdomain score significantly predicted 52% of the variance in LIPS-R Full-Scale IQ scores at follow-up, F(1, 34) = 35.80, p < .0001, R(2) = .52, ? = .72. This result suggests that the Visual Reception subscale offers predictive validity of later LIPS-R Full-Scale IQ scores. The VABS was also significantly correlated with cognitive variables at each time point.

Abstract

The Notch signaling pathway is thought to regulate multiple stages of inner ear development. Mutations in the Notch signaling pathway cause disruptions in the number and arrangement of hair cells and supporting cells in sensory regions of the ear. In this study we identify an insertional mutation in the mouse Sfswap gene, a putative splicing factor, that results in mice with vestibular and cochlear defects that are consistent with disrupted Notch signaling. Homozygous Sfswap mutants display hyperactivity and circling behavior consistent with vestibular defects, and significantly impaired hearing. The cochlea of newborn Sfswap mutant mice shows a significant reduction in outer hair cells and supporting cells and ectopic inner hair cells. This phenotype most closely resembles that seen in hypomorphic alleles of the Notch ligand Jagged1 (Jag1). We show that Jag1; Sfswap compound mutants have inner ear defects that are more severe than expected from simple additive effects of the single mutants, indicating a genetic interaction between Sfswap and Jag1. In addition, expression of genes involved in Notch signaling in the inner ear are reduced in Sfswap mutants. There is increased interest in how splicing affects inner ear development and function. Our work is one of the first studies to suggest that a putative splicing factor has specific effects on Notch signaling pathway members and inner ear development.

Abstract

The genetic diversity of loci and mutations underlying hereditary hearing loss is an active area of investigation. To identify loci associated with predominantly non-syndromic sensorineural hearing loss, we performed exome sequencing of families and of single probands, as well as copy number variation (CNV) mapping in a case-control cohort.Analysis of three distinct families revealed several candidate loci in two families and a single strong candidate gene, MYH7B, for hearing loss in one family. MYH7B encodes a Type II myosin, consistent with a role for cytoskeletal proteins in hearing. High-resolution genome-wide CNV analysis of 150 cases and 157 controls revealed deletions in genes known to be involved in hearing (e.g. GJB6, OTOA, and STRC, encoding connexin 30, otoancorin, and stereocilin, respectively), supporting CNV contributions to hearing loss phenotypes. Additionally, a novel region on chromosome 16 containing part of the PDXDC1 gene was found to be frequently deleted in hearing loss patients (OR = 3.91, 95% CI: 1.62-9.40, p = 1.45 x 10-7).We conclude that many known as well as novel loci and distinct types of mutations not typically tested in clinical settings can contribute to the etiology of hearing loss. Our study also demonstrates the challenges of exome sequencing and genome-wide CNV mapping for direct clinical application, and illustrates the need for functional and clinical follow-up as well as curated open-access databases.

Abstract

The outer hair cell (OHC) motor protein prestin is necessary for electromotility, which drives cochlear amplification and produces exquisitely sharp frequency tuning. Tecta(C1509G) transgenic mice have hearing loss, and surprisingly have increased OHC prestin levels. We hypothesized, therefore, that prestin up-regulation may represent a generalized response to compensate for a state of hearing loss. In the present study, we sought to determine the effects of noise-induced hearing loss on prestin expression. After noise exposure, we performed cytocochleograms and observed OHC loss only in the basal region of the cochlea. Next, we patch clamped OHCs from the apical turn (9-12 kHz region), where no OHCs were lost, in noise-exposed and age-matched control mice. The non-linear capacitance was significantly higher in noise-exposed mice, consistent with higher functional prestin levels. We then measured prestin protein and mRNA levels in whole-cochlea specimens. Both Western blot and qPCR studies demonstrated increased prestin expression after noise exposure. Finally, we examined the effect of the prestin increase in vivo following noise damage. Immediately after noise exposure, ABR and DPOAE thresholds were elevated by 30-40 dB. While most of the temporary threshold shifts recovered within 3 days, there were additional improvements over the next month. However, DPOAE magnitudes, basilar membrane vibration, and CAP tuning curve measurements from the 9-12 kHz cochlear region demonstrated no differences between noise-exposed mice and control mice. Taken together, these data indicate that prestin is up-regulated by 32-58% in residual OHCs after noise exposure and that the prestin is functional. These findings are consistent with the notion that prestin increases in an attempt to partially compensate for reduced force production because of missing OHCs. However, in regions where there is no OHC loss, the cochlea is able to compensate for the excess prestin in order to maintain stable auditory thresholds and frequency discrimination.

Abstract

The study of mouse hearing impairment mutants has led to the identification of a number of human hearing impairment genes and has greatly furthered our understanding of the physiology of hearing. The novel mouse mutant neurological/sensory 5 (nse5) demonstrates a significantly reduced or absent startle response to sound and is therefore a potential murine model of human hearing impairment. Genetic analysis of 500 intercross progeny localized the mutant locus to a 524 kilobase (kb) interval on mouse chromosome 15. A missense mutation in a highly-conserved amino acid was found in the asparagine-linked glycosylation 10B gene (Alg10b), which is within the critical interval for the nse5 mutation. A 20.4 kb transgene containing a wildtype copy of the Alg10b gene rescued the mutant phenotype in nse5/nse5 homozygous animals, confirming that the mutation in Alg10b is responsible for the nse5/nse5 mutant phenotype. Homozygous nse5/nse5 mutants had abnormal auditory brainstem responses (ABRs), distortion product otoacoustic emissions (DPOAEs), and cochlear microphonics (CMs). Endocochlear potentials (EPs), on the other hand, were normal. ABRs and DPOAEs also confirmed the rescue of the mutant nse5/nse5 phenotype by the wildtype Alg10b transgene. These results suggested a defect in the outer hair cells of mutant animals, which was confirmed by histologic analysis. This is the first report of mutation in a gene involved in the asparagine (N)-linked glycosylation pathway causing nonsyndromic hearing impairment, and it suggests that the hearing apparatus, and the outer hair cells in particular, are exquisitely sensitive to perturbations of the N-linked glycosylation pathway.

Abstract

To review the presentation and management of improper electrode array placement, and to help guide clinical decision-making.Retrospective case series.Pediatric and adult cochlear implant patients managed from January 2001 to present whose electrode arrays were not placed properly within the cochlea or extended beyond the cochlea into the internal auditory canal or adjacent structures.Four patients, three pediatric and one adult, were identified from over 824 cases (< 1%) managed over the study duration. All cases had normal cochlear anatomy. These cases were initially identified due to poor auditory skill development or absent behavioral responses following implantation, which prompted imaging. Two patients presented several years after surgery. Sites of improper placement included the eustachian tube, vestibule, internal carotid artery canal, and internal auditory canal (IAC). Intraoperative findings and management are reviewed.Electrode array malpositioning is a rare, but serious and correctable complication in cochlear implant surgery. A multidisciplinary approach, including prompt audiologic evaluation and imaging, is important, particularly when benefit from the implant is limited or absent. Management of electrode arrays in the IAC may be more challenging.

Abstract

Individuals with terminal and interstitial deletions of chromosome 1p36 have a spectrum of defects that includes eye anomalies, postnatal growth deficiency, structural brain anomalies, seizures, cognitive impairment, delayed motor development, behavior problems, hearing loss, cardiovascular malformations, cardiomyopathy, and renal anomalies. The proximal 1p36 genes that contribute to these defects have not been clearly delineated. The arginine-glutamic acid dipeptide (RE) repeats gene (RERE) is located in this region and encodes a nuclear receptor coregulator that plays a critical role in embryonic development as a positive regulator of retinoic acid signaling. Rere-null mice die of cardiac failure between E9.5 and E11.5. This limits their usefulness in studying the role of RERE in the latter stages of development and into adulthood. To overcome this limitation, we created an allelic series of RERE-deficient mice using an Rere-null allele, om, and a novel hypomorphic Rere allele, eyes3 (c.578T>C, p.Val193Ala), which we identified in an N-ethyl-N-nitrosourea (ENU)-based screen for autosomal recessive phenotypes. Analyses of these mice revealed microphthalmia, postnatal growth deficiency, brain hypoplasia, decreased numbers of neuronal nuclear antigen (NeuN)-positive hippocampal neurons, hearing loss, cardiovascular malformations-aortic arch anomalies, double outlet right ventricle, and transposition of the great arteries, and perimembranous ventricular septal defects-spontaneous development of cardiac fibrosis and renal agenesis. These findings suggest that RERE plays a critical role in the development and function of multiple organs including the eye, brain, inner ear, heart and kidney. It follows that haploinsufficiency of RERE may contribute-alone or in conjunction with other genetic, environmental, or stochastic factors-to the development of many of the phenotypes seen in individuals with terminal and interstitial deletions that include the proximal region of chromosome 1p36.

Abstract

Sound transduction within the auditory portion of the inner ear, the cochlea, is a complex nonlinear process. The study of cochlear mechanics in large rodents has provided important insights into cochlear function. However, technological and experimental limitations have restricted studies in mice due to their smaller cochlea. These challenges are important to overcome because of the wide variety of transgenic mouse strains with hearing loss mutations that are available for study. To accomplish this goal, we used spectral domain optical coherence tomography to visualize and measure sound-induced vibrations of intracochlear tissues. We present, to our knowledge, the first vibration measurements from the apex of an unopened mouse cochlea.

Abstract

Given the frequent use of improvised explosive devices (IEDs) around the world, the study of traumatic blast injuries is of increasing interest. The ear is the most common organ affected by blast injury because it is the body's most sensitive pressure transducer. We fabricated a blast chamber to re-create blast profiles similar to that of IEDs and used it to develop a reproducible mouse model to study blast-induced hearing loss. The tympanic membrane was perforated in all mice after blast exposure and found to heal spontaneously. Micro-computed tomography demonstrated no evidence for middle ear or otic capsule injuries; however, the healed tympanic membrane was thickened. Auditory brainstem response and distortion product otoacoustic emission threshold shifts were found to be correlated with blast intensity. As well, these threshold shifts were larger than those found in control mice that underwent surgical perforation of their tympanic membranes, indicating cochlear trauma. Histological studies one week and three months after the blast demonstrated no disruption or damage to the intra-cochlear membranes. However, there was loss of outer hair cells (OHCs) within the basal turn of the cochlea and decreased spiral ganglion neurons (SGNs) and afferent nerve synapses. Using our mouse model that recapitulates human IED exposure, our results identify that the mechanisms underlying blast-induced hearing loss does not include gross membranous rupture as is commonly believed. Instead, there is both OHC and SGN loss that produce auditory dysfunction.

Abstract

Early identification and management of disabilities in children are essential to reduce long-term developmental sequelae. Many of the causes of hearing loss also produce cognitive delays resulting in a large number of children with both deafness and developmental disabilities. Children who have hearing loss and additional disabilities require complex, individualized therapy to maximize their long-term quality of life. Hearing loss is often detected early because of widespread newborn hearing screening programs and the decision for cochlear implantation in children presenting with multiple medical and developmental disorders is still evolving. This article will review the literature regarding cochlear implant considerations in children with additional developmental disabilities in areas of family perception, speech and language development, cognitive development including adaptive behavior and intelligence, communication and functional skills, auditory outcomes, quality of life outcomes, predictors of outcomes and realistic expectations after cochlear implantation.

Abstract

The benefits of cochlear implantation for children with developmental delays (DD) often are unclear. We compared cognition, adaptive behavior, familial stress, and communication in children with and without DD.Retrospective review.Two tertiary care pediatric hospitals.Two hundred four children who underwent cochlear implantation assessed before and more than 1 year after implantation.The Mullen Scales of Early Learning (MSEL), vineland adaptive behavior scales (VABS), Parental Stress Index, and Preschool Language Scale.We developed a specific definition of DD for hearing-impaired children based upon diagnostic and statistical manual of mental disorders, fourth edition, criteria for mental retardation; 60 children met the criteria for DD, and 144 children did not. Before implantation, multiple linear regression demonstrated that children with DD had lower scores in every domain of the MSEL and VABS (p < 0.05), but no differences in any domains of the parental stress index and preschool language scale (p > 0.1) compared with children without DD. After implantation, children without DD demonstrated significant improvements in intelligence as measured by the MSEL and age-appropriate improvements in adaptive behavior as evaluated by the VABS, and their familial stress levels were not increased after cochlear implantation. In contrast, children with DD underwent implantation at a later age and demonstrated less comprehensive developmental improvements after cochlear implantation and higher stress levels. However, when the age differences were taken into account using multiple linear regression analyses, the differences between the 2 cohorts were reduced.These data indicate that our definition of DD is a reliable method of stratifying deaf children. Although children with DD have a normal developmental rate of adaptive behavior after cochlear implantation, their developmental rate of intelligence is lower, and they have higher stress levels than children without DD. However, our data suggest that if children with DD could be implanted as early as children without DD, their intelligence and stress outcomes would be improved.

Abstract

Many guidelines for reporting hearing results use the threshold at 3 kilohertz (kHz), a frequency not measured routinely. This study assessed the validity of estimating the missing 3-kHz threshold by averaging the measured thresholds at 2 and 4 kHz. The estimated threshold was compared to the measured threshold at 3 kHz individually and when used in the pure-tone average (PTA) of 0.5, 1, 2, and 3 kHz in audiometric data from 2170 patients. The difference between the estimated and measured thresholds for 3 kHz was within ± 5 dB in 72% of audiograms, ± 10 dB in 91%, and within ± 20 dB in 99% (correlation coefficient r = 0.965). The difference between the PTA threshold using the estimated threshold compared with using the measured threshold at 3 kHz was within ± 5 dB in 99% of audiograms (r = 0.997). The estimated threshold accurately approximates the measured threshold at 3 kHz, especially when incorporated into the PTA.

Abstract

The head bobber transgenic mouse line, produced by pronuclear integration, exhibits repetitive head tilting, circling behavior, and severe hearing loss. Transmitted as an autosomal recessive trait, the homozygote has vestibular and cochlea inner ear defects. The space between the semicircular canals is enclosed within the otic capsule creating a vacuous chamber with remnants of the semicircular canals, associated cristae, and vestibular organs. A poorly developed stria vascularis and endolymphatic duct is likely the cause for Reissner's membrane to collapse post-natally onto the organ of Corti in the cochlea. Molecular analyses identified a single integration of ~3 tandemly repeated copies of the transgene, a short duplicated segment of chromosome X and a 648 kb deletion of chromosome 7(F3). The three known genes (Gpr26, Cpxm2, and Chst15) in the deleted region are conserved in mammals and expressed in the wild-type inner ear during vestibular and cochlea development but are absent in homozygous mutant ears. We propose that genes critical for inner ear patterning and differentiation are lost at the head bobber locus and are candidate genes for human deafness and vestibular disorders.

Abstract

Inner ear hair cells are specialized sensory cells essential for auditory function. Previous studies have shown that the sensory epithelium is postmitotic, but it harbors cells that can behave as progenitor cells in vitro, including the ability to form new hair cells. Lgr5, a Wnt target gene, marks distinct supporting cell types in the neonatal cochlea. Here, we tested the hypothesis that Lgr5(+) cells are Wnt-responsive sensory precursor cells. In contrast to their quiescent in vivo behavior, Lgr5(+) cells isolated by flow cytometry from neonatal Lgr5(EGFP-CreERT2/+) mice proliferated and formed clonal colonies. After 10 d in culture, new sensory cells formed and displayed specific hair cell markers (myo7a, calretinin, parvalbumin, myo6) and stereocilia-like structures expressing F-actin and espin. In comparison with other supporting cells, Lgr5(+) cells were enriched precursors to myo7a(+) cells, most of which formed without mitotic division. Treatment with Wnt agonists increased proliferation and colony-formation capacity. Conversely, small-molecule inhibitors of Wnt signaling suppressed proliferation without compromising the myo7a(+) cells formed by direct differentiation. In vivo lineage tracing supported the idea that Lgr5(+) cells give rise to myo7a(+) hair cells in the neonatal Lgr5(EGFP-CreERT2/+) cochlea. In addition, overexpression of ?-catenin initiated proliferation and led to transient expansion of Lgr5(+) cells within the cochlear sensory epithelium. These results suggest that Lgr5 marks sensory precursors and that Wnt signaling can promote their proliferation and provide mechanistic insights into Wnt-responsive progenitor cells during sensory organ development.

Abstract

Vibratory measurements of the structures of the ear are key to understanding much of the pathology in mouse models of hearing loss. Unfortunately the high-speed sampling required to interrogate the high end of the mouse hearing spectrum is beyond the reach of most optical coherence tomography (OCT) systems. To address this issue, we have developed an algorithm that enables phase-sensitive OCT measurements over the full range of the mouse hearing spectrum (4-90 kHz). The algorithm phase-locks the line-trigger to the acoustic stimulation and then uses interleaved sampling to reconstruct the signal with higher temporal sampling. The algorithm was evaluated by measuring the vibratory response of mouse tympanic membrane to a pure tone stimulus.

Abstract

The tectorial membrane (TM) connects to the stereociliary bundles of outer hair cells (OHCs). Humans with an autosomal dominant C1509G mutation in alpha-tectorin, a protein constituent of the TM, are born with a partial hearing loss that worsens over time. The Tecta(C1509/+) transgenic mouse with the same point mutation has partial hearing loss secondary to a shortened TM that only contacts the first row of OHCs. As well, Tecta(C1509G/+) mice have increased expression of the OHC electromotility protein, prestin. We sought to determine whether these changes impact OHC survival. Distortion product otoacoustic emission thresholds in a quiet environment did not change to 6 months of age. However, noise exposure produced acute threshold shifts that fully recovered in Tecta (+/+) mice but only partially recovered in Tecta(C1509G/+) mice. While Tecta(+/+) mice lost OHCs primarily at the base and within all three rows, Tecta(C1509G/+) mice lost most of their OHCs in a more apical region of the cochlea and nearly completely within the first row. In order to estimate the impact of a shorter TM on the forces faced by the stereocilia within the first OHC row, both the wild type and the heterozygous conditions were simulated in a computational model. These analyses predicted that the shear force on the stereocilia is ~50% higher in the heterozygous condition. We then measured electrically induced movements of the reticular lamina in situ and found that while they decreased to the noise floor in prestin null mice, they were increased by 4.58 dB in Tecta(C1509G/+) mice compared to Tecta(+/+) mice. The increased movements were associated with a fourfold increase in OHC death as measured by vital dye staining. Together, these findings indicate that uncoupling the TM from some OHCs leads to partial hearing loss and places the remaining coupled OHCs at higher risk. Both the mechanics of the malformed TM and the increased prestin-related movements of the organ of Corti contribute to this higher risk profile.

Abstract

Measurements of human brain function in children are of increasing interest in cognitive neuroscience. Many techniques for brain mapping used in children, including functional near-infrared spectroscopy (fNIRS), electroencephalography (EEG), magnetoencephalography (MEG) and transcranial magnetic stimulation (TMS), use probes placed on or near the scalp. The distance between the scalp and the brain is a key variable for these techniques because optical, electrical and magnetic signals are attenuated by distance. However, little is known about how scalp-brain distance differs between different cortical regions in children or how it changes with development. We investigated scalp-brain distance in 71 children, from newborn to age 12 years, using structural T1-weighted MRI scans of the whole head. Three-dimensional reconstructions were created from the scalp surface to allow for accurate calculation of brain-scalp distance. Nine brain landmarks in different cortical regions were manually selected in each subject based on the published fNIRS literature. Significant effects were found for age, cortical region and hemisphere. Brain-scalp distances were lowest in young children, and increased with age to up to double the newborn distance. There were also dramatic differences between brain regions, with up to 50% differences between landmarks. In frontal and temporal regions, scalp-brain distances were significantly greater in the right hemisphere than in the left hemisphere. The largest contributors to developmental changes in brain-scalp distance were increases in the corticospinal fluid (CSF) and inner table of the cranium. These results have important implications for functional imaging studies of children: age and brain-region related differences in fNIRS signals could be due to the confounding factor of brain-scalp distance and not true differences in brain activity.

Abstract

Human hearing loss often occurs as a result of damage or malformations to the functional soft tissues within the cochlea, but these changes are not appreciable with current medical imaging modalities. We sought to determine whether optical coherence tomography (OCT) could assess the soft tissue structures relevant to hearing using mouse models. We imaged excised cochleae with an altered tectorial membrane and during normal development. The soft tissue structures and expected anatomical variations were visible using OCT, and quantitative measurements confirmed the ability to detect critical changes relevant to hearing.

Abstract

To examine middle ear volume in patients with aural atresia and investigate the role of middle ear volume as an adjunct measure in determining surgical candidacy.We performed a retrospective review of children with aural atresia in a tertiary academic pediatric otolaryngology practice. High resolution multiplanar CT scans of the temporal bones were analyzed for middle ear volume and staged according to existing clinical grading scales. Atretic ears were compared to the nonatretic ears of the same patient as well as to ears of a control population.The average age of patients at the time CT was performed was 4.7 years (range <0.1-13.8 years). The average middle ear volume of the atretic ears was 0.34 cc compared to an average of 0.51 cc for the nonatretic ears. The mean ratio of the atretic to nonatretic volume was 0.67. In patients who underwent serial scans, no statistically significant difference in rates of growth existed between atretic and nonatretic ears. Finally, measures of middle ear volume correlated well with clinical grading scales.Both middle ear volume and the ratio of the atretic volume to nonatretic volume serve as useful adjunct measurements in determining surgical candidacy. The practitioner may be better able to assess surgical candidacy by supplementing classic atresia classification systems with middle ear volume measurements.

Abstract

The tectorial membrane (TM) is an extracellular matrix of the cochlea whose prominent role in hearing has been demonstrated through mutation studies. The C1509G mutation of the Tecta gene, which encodes for the ?-tectorin protein, leads to hearing loss. The heterozygote TM only attaches to the first row of outer hair cells (OHCs), and the homozygote TM does not attach to any OHCs. Here we measured the morphology and mechanical properties of wild-type, heterozygous, and homozygous Tecta TMs. Morphological analyses conducted with second- and third-harmonic imaging, scanning electron microscopy, and immunolabeling revealed marked changes in the collagen architecture and stereocilin-labeling patterns of the mutant TMs. The mechanical properties of the mutant TM were measured by force spectroscopy. Whereas the axial Young's modulus of the low-frequency (apical) region of Tecta mutant TM samples was similar to that of wild-type TMs, it significantly decreased in the basal region to a value approaching that found at the apex. Modeling simulations suggest that a reduced TM Young's modulus is likely to reduce OHC stereociliary deflection. These findings argue that the heterozygote C1509G mutation results in a lack of attachment of the TM to the OHCs, which in turn reduces both the overall number of OHCs that are involved in mechanotransduction and the degree of mechanotransduction exhibited by the OHCs that remain attached to the TM.

Abstract

Selection of diagnostic tests for children with sensorineural hearing loss (SNHL) is influenced by clinical suspicion. Testing results reported in the literature are similarly biased. We evaluate the usefulness of a comprehensive diagnostic battery for each child.Retrospective review.Tertiary care university hospital.A total of 270 children referred for severe to profound SNHL between January 2002 and June 2009.Results of the following were reviewed: magnetic resonance imaging, computed tomography, renal ultrasound, electrocardiography, fluorescent treponemal antibody absorption test, connexin 26 sequencing, genetic consultation, and ophthalmologic consultation.Diagnostic yield of each test was determined.Each diagnostic test or consultation was completed by at least 95% of patients for whom it was ordered. Magnetic resonance imaging revealed abnormalities explaining SNHL in 24% of patients. Computed tomography showed inner ear anomalies in 18% of patients. Biallelic connexin 26 mutations were found in 15%. Renal ultrasound found anomalies in 4% of patients. Electrocardiography found 1% of patients with prolonged QT intervals. Fluorescent treponemal antibody absorption test result was positive in 0.5%. Genetic consultation found a genetic cause for hearing loss in 25%. Ophthalmologic consultation found abnormalities associated with hearing loss in 8%.Diagnostic radiologic imaging is the highest yielding test for evaluating children with SNHL. Connexin 26 sequencing identifies a nearly nonoverlapping subset of children compared with imaging. Specialty consultations, particularly from a clinical geneticist, can improve diagnostic yield. Other tests, although of lower diagnostic yield for SNHL, can identify important diseases that significantly affect patient health.

Abstract

This article reviews the clinical approach taken towards identification of the cause of hearing loss in children. A brief overview of the universal newborn hearing screening program is presented. Discussion is then focused on clinical elements of the diagnostic process with emphasis on the importance of the history, physical examination, and audiologic testing. The utility and appropriateness of additional diagnostic testing is considered, particularly with regards to the incorporation of diagnostic radiologic imaging and genetic testing. In the course of these discussions, the genetic and non-genetic causes of pediatric hearing loss are reviewed. Finally, the implications of a definitive identification of hearing loss etiology are considered.

Abstract

Cochlear implants (CI) are commonly used to treat deafness in young children. While many factors influence the ability of a deaf child who is hearing through a CI to develop speech and language skills, an important factor is that the CI has to stimulate the auditory cortex. Obtaining behavioral measurements from young children with CIs can often be unreliable. While a variety of noninvasive techniques can be used for detecting cortical activity in response to auditory stimuli, many have critical limitations when applied to the pediatric CI population. We tested the ability of near-infrared spectroscopy (NIRS) to detect cortical responses to speech stimuli in pediatric CI users. Neuronal activity leads to changes in blood oxy- and deoxy-hemoglobin concentrations that can be detected by measuring the transmission of near-infrared light through the tissue. To verify the efficacy of NIRS, we first compared auditory cortex responses measured with NIRS and fMRI in normal-hearing adults. We then examined four different participant cohorts with NIRS alone. Speech-evoked cortical activity was observed in 100% of normal-hearing adults (11 of 11), 82% of normal-hearing children (9 of 11), 78% of deaf children who have used a CI > 4 months (28 of 36), and 78% of deaf children who completed NIRS testing on the day of CI initial activation (7 of 9). Therefore, NIRS can measure cortical responses in pediatric CI users, and has the potential to be a powerful adjunct to current CI assessment tools.

Abstract

Most forms of hearing loss are associated with loss of cochlear outer hair cells (OHCs). OHCs require the tectorial membrane (TM) for stereociliary bundle stimulation (forward transduction) and active feedback (reverse transduction). Alpha tectorin is a protein constituent of the TM and the C1509G mutation in alpha tectorin in humans results in autosomal dominant hearing loss. We engineered and validated this mutation in mice and found that the TM was shortened in heterozygous Tecta(C1509G/+) mice, reaching only the first row of OHCs. Thus, deficient forward transduction renders OHCs within the second and third rows non-functional, producing partial hearing loss. Surprisingly, both Tecta(C1509G/+) and Tecta(C1509G/C1509G) mice were found to have increased reverse transduction as assessed by sound- and electrically-evoked otoacoustic emissions. We show that an increase in prestin, a protein necessary for electromotility, in all three rows of OHCs underlies this phenomenon. This mouse model demonstrates a human hearing loss mutation in which OHC function is altered through a non-cell-autonomous variation in prestin.

Abstract

To examine the characteristics of pediatric cochlear implant channel malfunction preceding device failure.: Retrospective review.All pediatric patients who underwent cochlear implantation at a tertiary academic medical center were reviewed regarding device type, reason for replacement, time to replacement, and timing and pattern of channel faults in failed versus nonfailed devices.Between 1993 and 2008, 264 pediatric cochlear implantations were performed. With an average 894-day follow-up, the replacement rate was 9.5% (25/264). Reasons for replacement were device failure (6.4%), medical/surgical failure (2.3%), and obsolescence (0.8%). Replacement rates were comparable among Advanced Bionics (13.3%), Cochlear Corporation (6.3%), and MED-EL (10.3%) devices. Fifty-two cochlear implants developed at least one channel fault, and 13 eventually progressed to failure requiring replacement. MED-EL devices comprised 12 of these 13 failures. At the 12-month follow-up interval, one, three, and five channel faults predicted 40%, 75%, and 100% probabilities of eventual electrode failure, respectively. Channels destined to fail demonstrated small, yet statistically significant, impedance elevations 12 months before failure and large elevations 3 months before failure.Replacement of cochlear implants in pediatric patients is common and is due to device malfunction about one half of the time. Earlier initial channel fault, earlier subsequent channel faults, adjacent channel faults, and a greater total number of channel faults were associated with the need for replacement surgery. Elevations in a channel's impedance should raise the concern for an impending failure. These predictors can help the cochlear implant team when considering surgery to replace the device.

Abstract

Mice are an excellent model for studying mammalian hearing and transgenic mouse models of human hearing, loss are commonly available. However, the mouse cochlea is substantially smaller than other animal models routinely used to study cochlear physiology. This makes study of their hair cells difficult. We develop a novel methodology to optically image calcium within living hair cells left undisturbed within the excised mouse cochlea. Fresh cochleae are harvested, left intact within their otic capsule bone, and fixed in a recording chamber. The bone overlying the cochlear epithelium is opened and Reissner's membrane is incised. A fluorescent calcium indicator is applied to the preparation. A custom-built upright two-photon microscope was used to image the preparation using 3-D scanning. We are able to image about one third of a cochlear turn simultaneously, in either the apical or basal regions. Within one hour of animal sacrifice, we find that outer hair cells demonstrate increased fluorescence compared with surrounding supporting cells. This methodology is then used to visualize hair cell calcium changes during mechanotransduction over a region of the epithelium. Because the epithelium is left within the cochlea, dissection trauma is minimized and artifactual changes in hair cell physiology are expected to be reduced.

Abstract

Previous studies have demonstrated consistent benefit in older adults undergoing cochlear implantation as compared with younger control groups, with age category thresholds between 60 and 70 years. The objective of this study is to report auditory performance in implant recipients older than 75 years, a cohort for which few data have been reported.Retrospective chart review.Academic cochlear implant program in a tertiary-care hospital.: Twenty-eight cochlear implant recipients were subdivided into implant users older than 80 years (Group 1) and recipients currently older than 75 years (Group 2).Cochlear implantation.Open-set speech perception scores.: Postoperative open-set speech perception scores were compared with preoperative scores in the best-aided condition. Criteria were developed to define situations where the implant was considered to be nonbeneficial or less beneficial than amplification, and those data were then subjected to Kaplan-Meier analysis.Group 1 included 13 patients with mean age of 80.7 years at the time of implantation. Group 2 included 15 patients with a mean age of 71.6 years. Scores were significantly better postoperatively at 6 months (p < 0.01) for Group 2 and at 12 months (p < 0.01) for both Groups 1 and 2. Kaplan-Meier curves were constructed for both groups.Cochlear implantation in patients older than 75 years is beneficial, and Kaplan-Meier analysis demonstrates that the clinical benefit is durable over time. Patients older than 80 years obtain similar benefit, although auditory performance was less robust.

Abstract

Atoh1 is a basic helix-loop-helix transcription factor necessary for the specification of inner ear hair cells and central auditory system neurons derived from the rhombic lip. We used the Cre-loxP system and two Cre-driver lines (Egr2(Cre) and Hoxb1(Cre)) to delete Atoh1 from different regions of the cochlear nucleus (CN) and accessory auditory nuclei (AAN). Adult Atoh1-conditional knock-out mice (Atoh1(CKO)) are behaviorally deaf, have diminished auditory brainstem evoked responses, and have disrupted CN and AAN morphology and connectivity. In addition, Egr2; Atoh1(CKO) mice lose spiral ganglion neurons in the cochlea and AAN neurons during the first 3 d of life, revealing a novel critical period in the development of these neurons. These new mouse models of predominantly central deafness illuminate the importance of the CN for support of a subset of peripheral and central auditory neurons.

Abstract

Recently, several groups have noticed an increase in cases of advanced pediatric mastoiditis and intracranial complications. The objective of this study was to review the bacteriology of advanced mastoiditis in pediatric patients, with the hypothesis that a difference in bacteriology might explain the development of an intracranial complication.Retrospective chart review.All pediatric patients with coalescent mastoiditis requiring surgery treated at a tertiary care children's hospital between 2002 and 2007 were reviewed. Every patient included was treated either with mastoidectomy alone (for coalescent mastoiditis without an intracranial complication) or with transtemporal craniotomy (for coalescent mastoiditis with an intracranial complication). All patients had surgical specimens sent for pathology, Gram stain, and aerobic and anaerobic cultures.One hundred eight pediatric patients with coalescent mastoiditis were identified: 58 (53%) presented with coalescent mastoiditis alone, 17 (16%) presented with coalescent mastoiditis and an intracranial complication, and 33 (31%) were excluded because they were treated with myringotomy and tubes alone, had incomplete data, or had an unclear diagnosis. Streptococcus pneumoniae was the most commonly cultured organism in patients with and without intracranial complications. Anaerobic isolates were present in 29.4% of patients with intracranial complications and 5.7% of patients without intracranial complications (P = .015).Nearly a quarter of pediatric patients with coalescent mastoiditis presented with a simultaneous intracranial complication. There was an increased incidence of anaerobic organisms in patients with intracranial complications compared to those without, indicating the importance of culture and antibiotic coverage appropriate for anaerobes. This series demonstrates the role of aggressive surgical management and close collaboration with the infectious disease service for long-term intravenous antibiotic therapy in treating pediatric patients with advanced mastoiditis.

Abstract

The objective of this study was to determine if intra-operative auditory monitoring is feasible during cochlear implantation and whether this can be used as feedback to the surgeon to improve the preservation of residual hearing. This prospective non-randomised study was set in a paediatric tertiary referral hospital. Thirty eight consecutive paediatric patients undergoing cochlear implantation who had measurable auditory thresholds pre-operatively were divided into two cohorts. The unmonitored cohort included the first 22 patients and the monitored cohort included the last 16 patients. The main outcome measure(s) were pre-operative, intra-operative and more than one month post-operative average auditory thresholds at 500, 1000 and 2000 Hz measured using auditory steady-state response audiometry. The average pre-operative thresholds were 103.5 dB HL and 99.7 dB HL in the unmonitored and monitored cohorts, respectively. These were not statistically different (p > 0.3). In the monitored cohort, we measured auditory thresholds to assess cochlear function at multiple time points during the operation. Compared to baseline, thresholds were increased 0.7 dB after drilling the mastoidectomy and well, 0.2 dB after opening the cochlea and 4.6 dB after inserting the electrode array. One month post-operatively, the average thresholds were 114.0 dB HL in the unmonitored cohort but only 98.8 dB HL in the monitored cohort (p < 0.001). Both the use of intra-operative auditory monitoring and higher pre-operative thresholds were associated with improved preservation of residual hearing (p

Abstract

This case study describes the neurocognitive presentation of a child with identified genetic abnormalities of trisomy 6 and monosomy 21 who was evaluated as part of a standard medical protocol for cochlear implantation following diagnosis of profound sensorineural hearing loss. This child received neurocognitive testing prior to cochlear implantation and approximately 12 months post-activation of his cochlear implant. While he has not fully developed oral language, his presentation suggested improvement in overall skills since the activation of the cochlear implant; however, less than would be expected for a typically developing child.

Hearing loss in children with very low birth weight: current review of epidemiology and pathophysiology.Archives of disease in childhood. Fetal and neonatal editionCristobal, R., Oghalai, J. S.2008; 93 (6): F462-8

Abstract

An association between birth weight <1500 g (very low birth weight (VLBW)) and hearing loss has been long recognised. As universal hearing screening programmes have become widely implemented and the survival rate of VLBW babies in modern intensive care units has increased, we have gained a substantially better understanding of the nature of this problem. However, many gaps in our knowledge base exist. This review describes recent data on hearing loss in the VLBW population and explains the current level of understanding about the physiological basis underlying the auditory deficits in these patients. Although VLBW alone may not have a severe impact on hearing, it is commonly associated with multiple other risk factors that can alter hearing in a synergistic fashion. Therefore, the risk of hearing loss is substantially higher than in the general newborn population. Also, it is important to perform a more comprehensive audiometric evaluation than standard otoacoustic emission screening for infants who are in the neonatal intensive care unit in order not to miss hearing loss due to retrocochlear pathology. Furthermore, children with VLBW are also at increased risk of experiencing progressive or delayed-onset hearing loss, and thus should continue to have serial hearing evaluations after discharge from the neonatal intensive care unit.

Hearing loss in children with very low birth weight: current review of epidemiology and pathophysiologyARCHIVES OF DISEASE IN CHILDHOOD-FETAL AND NEONATAL EDITIONCristobal, R., Oghalai, J. S.2008; 93 (6): 1462-1468

Abstract

The cochlear amplifier is required for the exquisite sensitivity of mammalian hearing. Outer hair cells underlie the cochlear amplifier and they are unique in that they maintain an intracellular turgor pressure. Changing the turgor pressure of an isolated outer hair cells through osmotic challenge modulates its ability to produce electromotile force. We sought to determine the effect of osmotic challenge on cochlear function.In vivo animal study.Hypotonic and hypertonic artificial perilymph was perfused through the scala tympani of anesthetized guinea pigs. Cochlear function was assessed by measuring the compound action potential, distortion product otoacoustic emissions, the cochlear microphonic, and the endocochlear potential.Hypotonic perilymph decreased and hypertonic perilymph increased compound action potential and distortion product otoacoustic emission thresholds in a dose-dependent and reversible manner. The cochlear microphonic quadratic distortion product magnitude increased after hypotonic perfusion and decreased with hypertonic perfusion. There were no changes in the stimulus intensity growth curve of the low-frequency cochlear microphonic. The endocochlear potential was not affected by perilymph osmolality.These data demonstrate that perilymph osmolality can modulate cochlear function and are consistent with what would be expected if outer hair cells turgor pressure changes the gain of the cochlear amplifier in vivo.

Abstract

Prestin is a membrane protein in the outer hair cell (OHC) that has been shown to be essential for electromotility. OHCs from prestin-null mice do not express prestin, do not have a nonlinear capacitance (the electrical signature of electromotility), and are smaller in size than wild-type OHCs. We sought to determine whether prestin-null OHCs can be transduced to incorporate functional prestin protein in a normal fashion. A recombinant helper-dependent adenovirus expressing prestin and green fluorescent protein (HDAd-prestin-GFP) was created and tested in human embryonic kidney cells (HEK cells). Transduced HEK cells demonstrated membrane expression of prestin and nonlinear capacitance. HDAd-prestin-GFP was then applied to cochlear sensory epithelium explants harvested from wild-type and prestin-null mice at postnatal days 2-3, the age at which native prestin is just beginning to become functional in wild-type mice. At postnatal days 4-5, we investigated transduced OHCs for (1) their prestin expression pattern as revealed by immunofluorescence; (2) their cell surface area as measured by linear capacitance; and (3) their prestin function as indicated by nonlinear capacitance. HDAd-prestin-GFP efficiently transduced OHCs of both genotypes and prestin protein localized to the plasma membrane. Whole-cell voltage clamp studies revealed a nonlinear capacitance in transduced wild-type and prestin-null OHCs, but not in non-transduced cells of either genotype. Prestin transduction did not increase the linear capacitance (cell surface area) for either genotype. In peak nonlinear capacitance, voltage at peak nonlinear capacitance, charge density of the nonlinear capacitance, and shape of the voltage-capacitance curves, the transduced cells of the two genotypes resembled each other and previously reported data from adult wild-type mouse OHCs. Thus, prestin introduced into prestin-deficient OHCs segregates normally to the cell membrane and generates a normal nonlinear capacitance, indicative of normal prestin function.

Abstract

Cholesterol affects diverse biological processes, in many cases by modulating the function of integral membrane proteins. We observed that alterations of cochlear cholesterol modulate hearing in mice. Mammalian hearing is powered by outer hair cell (OHC) electromotility, a membrane-based motor mechanism that resides in the OHC lateral wall. We show that membrane cholesterol decreases during maturation of OHCs. To study the effects of cholesterol on hearing at the molecular level, we altered cholesterol levels in the OHC wall, which contains the membrane protein prestin. We show a dynamic and reversible relationship between membrane cholesterol levels and voltage dependence of prestin-associated charge movement in both OHCs and prestin-transfected HEK 293 cells. Cholesterol levels also modulate the distribution of prestin within plasma membrane microdomains and affect prestin self-association in HEK 293 cells. These findings indicate that alterations in membrane cholesterol affect prestin function and functionally tune the outer hair cell.

Abstract

Gene therapy may provide a way to restore cochlear function to deaf patients. The most successful techniques for cochlear gene therapy have been injection of early-generation adenoviral vectors into scala media in guinea pigs. However, it is important to be able to perform gene therapy research in mice because there is wide availability of transgenic strains with hereditary hearing loss.We demonstrate our technique for delivery of a third-generation adenoviral vector, helper-dependent adenovirus (HDAd), to the adult mouse cochlea.Mice were injected with an HDAd that contained a reporter gene for either beta-galactosidase or green fluorescent protein into scala media. After 4 days, the cochleae were harvested for analyses. Auditory brainstem response monitoring of cochlear function was performed before making a cochleostomy, after making a cochleostomy, and before killing the animal.Beta-galactosidase was identified in the spiral ligament, the organ of Corti, and spiral ganglion cells by light microscopy. Green fluorescent protein epifluorescence was assessed in whole-mount organ of Corti preparations using confocal microscopy. This demonstrated transduction of inner hair cells, outer hair cells, and supporting cells. Paraffin-embedded cross sections similarly revealed gene transduction within the organ of Corti. Threshold shifts of 39.8 +/- 5.4 and 37.7 +/- 5.5 dB were observed in mice injected with HDAd or control buffer, respectively.The technique of scala media HDAd injection reliably infects the adult mouse cochlea, including cells within the organ of Corti, although the procedure itself adversely affects hearing.

Abstract

The BETA2/NeuroD1 null mouse has cochlear dysplasia. Its cochlear duct is shorter than normal, there is a lack of spiral ganglion neurons, and there is hair cell disorganization. We measured vertical movements of the tectorial membrane at acoustic frequencies in excised cochleae in response to mechanical stimulation of the stapes using laser doppler vibrometry. While tuning curve sharpness was similar between wild-type, heterozygotes, and null mice in the base, null mutants had broader tuning in the apex. At both the base and the apex, null mice had less phase lag accumulation with increasing stimulus frequency than wild-type or heterozygote mice. In vivo studies demonstrated that the null mouse lacked distortion product otoacoustic emissions, and the cochlear microphonic and endocochlear potential were found to be severely reduced. Electrically evoked otoacoustic emissions could be elicited, although the amplitudes were lower than those of wild-type mice. Cochlear cross-sections revealed an incomplete partition malformation, with fenestrations within the modiolus that connected the cochlear turns. Outer hair cells from null mice demonstrated the normal pattern of prestin expression within their lateral walls and normal FM 1-43 dye entry. Overall, these data demonstrate that while tonotopicity can exist with cochlear dysplasia, traveling wave propagation is abnormally fast. Additionally, the presence of electrically evoked otoacoustic emissions suggests that outer hair cell reverse transduction is present, although the acoustic response is shaped by the alterations in cochlear mechanics.

Abstract

The present review summarizes the current theories on arachnoid cyst formation, the common presentations of cysts surrounding or eroding the temporal bone from the middle and posterior cranial fossae, the diagnostic strategies and the management considerations and options.Arachnoid cysts are most common in the middle cranial fossa and rarely present in association with the petrous apex. They are frequently found incidentally on imaging studies performed in the workup for unrelated symptoms. When they do cause symptoms, these are usually nonspecific. Thus it is important to establish the relationship between the two. Peripetrosal arachnoid cysts may cause cranial nerve deficits in addition to symptoms related to intracranial hypertension. Small asymptomatic cysts are managed conservatively with serial imaging. Large symptomatic cysts are often managed surgically with shunting, open excision or open or neuroendoscopic fenestration or marsupialization. The management of large asymptomatic cysts depends on the patient and cyst characteristics.Peripetrosal arachnoid cysts are often incidental findings. Careful selection of surgical candidates is of utmost importance. Multiple surgical options with similar success rates are available. The rates and profile of their complications may differ. Overall, approximately 70% of patients experience improvement in their symptoms with surgery.

Abstract

A considerable amount of literature has documented the impact of hearing impairment on spoken language skills in deaf children referred for cochlear implantation. Critical areas of neurocognitive development in the acquisition of visual (manual) language also appear to be impacted, although the evidence is less robust. The present study focused on the development of visual and fine motor skills in a sample of preschool-age children diagnosed with sensorineural hearing loss with no known neurologic conditions (n=36).Analysis of data collected as part of a standardized screening process for cochlear implantation at an academic medical center.Children underwent a standardized neuropsychological assessment battery. Children were classified into three groups based on the etiology of their deafness (Connexin=15, Structural Malformation=11, and Unknown=10).Correlational analyses replicated previous research on the reduction in visual reception and fine motor skills as deaf children age. Children with genetic (Connexin) etiology exhibited a significant reduction in fine motor skills with age, whereas those with an etiology of Structural Abnormality exhibited a significant reduction in visual reception skills with age. Results of planned comparisons conducted as part of a multivariate analysis of variance (Skill x Group) indicated that the Connexin group was significantly better than the Unknown group with regard to fine motor skills. Implications for these findings and future studies are discussed.

Abstract

Cognitive ability and behavioral adaptability are distinct, yet related, constructs that can impact childhood development. Both are often reduced in deaf children of hearing parents who do not provide sufficient language and communication access. Additionally, parental depression is commonly observed due to parent-child communication difficulties that can lead to parents' feelings of inadequacy and frustration. We sought to assess whether adaptive behavior in deaf children was associated with nonverbal intelligence and parental depression. Parents of precochlear implant patients seen for neuropsychological assessment were administered the Parenting Stress Index and Vineland Behavior Adaptive Scales to obtain measures of parental distress and child's behavioral adaptability. Precochlear implant patients' cognitive functioning was assessed via the Mullen Scales of Early Learning or the Leiter International Performance Scale-Revised, depending on the child's age at the time of testing. Regardless of age or neurological status, the deaf child's adaptive behavior consistently showed a strong relationship with intelligence. Moderate correlation between parental depression and the child's adaptive behavior was observed only in the younger group. The relationship between parental depression and communication subscale was moderated by intelligence for deaf children without neurological complications. The findings provide important implications for promoting family-centered interventions with early communication and language development.

Abstract

Objective: To describe and illustrate three distinct surgical approaches that permit exposure and resection of extradural, intradural, and transdural lesions involving the hypoglossal canal. Study design: Case series. Setting: University medical center. Patients: Four patients with lesions of the hypoglossal canal were reviewed to illustrate our philosophy when selecting a surgical approach to the hypoglossal canal. Interventions: Three separate surgical approaches were used to approach lesions involving various segments of the hypoglossal canal. Main outcome measures: Initial clinical presentation, tumor type, treatment course, complications and functional outcomes of hearing, lower cranial nerves, and great vessels. Results: A modified pre- and postauricular infratemporal fossa approach was used to permit the complete resection of an extradural hypoglossal canal schwannoma. The far lateral approach was used to remove a posterior fossa meningioma that involved the intradural hypoglossal canal. A transjugular craniotomy was used to resect a jugulotympanic paraganglioma with transdural hypoglossal canal involvement. Postoperatively, there were no major complications. However, one patient had cerebrospinal fluid rhinorrhea that resolved with lumbar subarachnoid drainage and another had a pseudomeningocele that resolved spontaneously. Dysphagia was not observed in any patient and all were discharged within 1 week of surgery. All patients are free of recurrence by clinical and radiographic examination with at least 2 years of follow-up. Conclusions: Lesions of the hypoglossal canal can be safely and effectively resected using the appropriate skull base approach. The three skull base approaches described herein provide access to selected portions of the hypoglossal canal and allow for preservation of hearing, the lower cranial nerves, and great vessels.

Abstract

The cochlea is the mammalian organ of hearing. Its predominant vibratory element, the basilar membrane, is tonotopically tuned, based on the spatial variation of its mass and stiffness. The constituent collagen fibers of the basilar membrane affect its stiffness. Laser irradiation can induce collagen remodeling and deposition in various tissues. We tested whether similar effects could be induced within the basilar membrane. Trypan blue was perfused into the scala tympani of anesthetized mice to stain the basilar membrane. We then irradiated the cochleas with a 694-nm pulsed ruby laser at 15 or 180 Jcm(2). The mice were sacrificed 14 to 16 days later and collagen organization was studied. Polarization microscopy revealed that laser irradiation increased the birefringence within the basilar membrane in a dose-dependent manner. Electron microscopy demonstrated an increase in the density of collagen fibers and the deposition of new fibrils between collagen fibers after laser irradiation. As an assessment of hearing, auditory brainstem response (ABR) thresholds were found to increase moderately after 15 Jcm(2) and substantially after 180 Jcm(2). Our results demonstrate that collagen remodeling and new collagen deposition occurs within the basilar membrane after laser irradiation in a similar fashion to that found in other tissues.

Abstract

To describe the presentation, diagnostic evaluation, and surgical management of petrous apex cerebrospinal fluid (CSF) cysts and cephaloceles.Retrospective case review.Tertiary referral center.Six patients with symptomatic CSF cysts or cephaloceles.All patients underwent operative intervention.Presentation, imaging characteristics, operative findings, surgical approach, resolution of symptoms, and complications.Six patients presented with various neurotologic symptoms including vertigo, otalgia, diplopia, meningitis, hearing loss, and retroorbital headaches. Four lesions were centered within the anterior petrous apex and were classified as a cephalocele originating from Meckel's cave. The remaining two lesions were arachnoid cysts that involved the posterior petrous apex. Cysts and cephaloceles both demonstrated bone erosion on computed tomography and were hyperintense on T2-weighted magnetic resonance imaging and isointense or hypointense on T1-weighted magnetic resonance imaging. A variety of surgical approaches was used to treat these lesions. Preoperative symptoms were improved in five of six cases. One patient developed a postoperative CSF leak that resolved with conservative measures.Petrous apex CSF cysts and cephaloceles may present with a variety of neurotologic symptoms. Imaging often helps narrow the differential diagnosis, but these lesions can still be confused with other erosive skull base lesions such as cholesterol granulomas, epidermoids, or tumors. Optimal treatment of symptomatic posterior petrous apex CSF cysts is marsupialization via a posterior fossa approach (i.e., retrosigmoid or retrolabyrinthine). A middle fossa approach with obliteration of the anterior petrous apex may be used to treat symptomatic CSF cephaloceles arising from Meckel's cave.

Abstract

Mutations in GJB2 are associated with hereditary hearing loss. DNA sequencing of GJB2 in a cohort of hearing impaired patients and a multi-ethnic control group is reported. Among 610 hearing impaired cases, 43 DNA sequence variations were identified in the coding region of GJB2 including 24 mutations, 8 polymorphisms, 3 unclassified variants (G4D, R127C, M163V), 1 controversial variant (V37I), and 7 novel variants (G12C, N14D, V63A, T86M, L132V, D159, 592_600delinsCAGTGTTCATGACATTC). Sixteen non-coding sequence variations were also identified among cases including the IVS1+1A>G mutation, 2 polymorphisms, and 13 novel variants. A diagnosis of GJB2-associated hearing loss was confirmed for 63 cases (10.3%). Heterozygous mutations were found in 39 cases (6.4%). Eleven cases carrying novel or unclassified variants (1.8 %) and 18 cases carrying the controversial V37I variant were identified (3%). In addition, 294 control subjects from 4 ethnic groups were sequenced for GJB2. Thirteen sequence variations in the coding region of GJB2 were identified among controls including 2 mutations, 6 polymorphisms, 2 unclassified variants (G4D, T123N), 1 controversial variant (V37I), and 2 novel variants (R127L, V207L). Nine sequence variations were identified among controls in the non-coding regions in and around GJB2 exon 2. Of particular interest among controls were the variability in carrier rates and ethnic stratification of alleles, and the complex genotypes among Asians, 47% of whom carried two to four sequence variations in the coding region of GJB2. These data provide new information about carrier rates for GJB2-based hearing loss in various ethnic groups and contribute to evaluation of the pathogenicity of the controversial V37I variant.

Abstract

Petrous apicitis and cranial base osteomyelitis are life-threatening conditions. A surgical management may be necessary in cases that progress, in conditions that fail to improve with medical treatment, or in cases with impending complications. In this study, we describe a technique to remove the maximum amount of infected temporal bone while preserving the integrity of the peripheral auditory pathway and facial nerve.Retrospective study.Tertiary referral hospital.Five patients with impending complications, whose disease progressed or whose conditions failed to improve while on culture-directed antibiotics underwent circumferential petrosectomy.The circumferential petrosectomy removes most of the temporal bone around the external, middle, and inner ear. A combined retrolabyrinthine-apical petrosectomy is performed in conjunction with the fallopian bridge technique using a transmastoid and middle cranial fossa approach. A split temporalis muscle flap is used to bring vascularized tissue to the mastoid, jugular foramen, and petrous apex.Disease resolution, change in hearing or facial nerve function, complications.Each of the five patients had modifications to the procedure tailored to their disease extent: three had disease primarily involving the petrous apex and two had disease adjacent to the jugular foramen. Additional cultures of the infected bone were obtained during surgery. A culture-directed antibiotic therapy (duration, 6-10 weeks) was administered after surgery, which resulted in the complete resolution of the disease and the associated symptoms in all five patients. No patient experienced hearing loss or facial nerve dysfunction as a result of the surgery within at least 1 year of follow-up in four of the five patients in this series.The circumferential petrosectomy is a potential treatment option when medical treatment fails in patients with petrositis or cranial base osteomyelitis. It permits maximal temporal bone debridement while preserving hearing and facial nerve integrity in these life-threatening disease processes.

Abstract

The relationship between dyslipidemia and hearing is unclear. This study was conducted to investigate whether elevated serum lipid levels impact auditory function in humans and in guinea pigs. In the human study, a cross-sectional study of 40 volunteers with dyslipidemia was conducted. Pure tone thresholds, distortion product otoacoustic emissions, and lipid profiles were analyzed. When controlled for patient age and sex, we found that elevated triglycerides were associated with reduced hearing. In the guinea pig study, a prospective study of animals fed a high-fat diet for 14 weeks was conducted. Although the high-fat diet led to a dramatic elevation in the average weight and total cholesterol in all animals (from 61 to 589 mg/dl), there were no meaningful changes in distortion product otoacoustic emission magnitudes. These results suggest that whereas chronic dyslipidemia associated with elevated triglycerides may reduce auditory function, short-term dietary changes may not.

Abstract

Cochlear outer hair cells (OHCs) are polarized epithelial cells that have mechanoelectrical transduction channels within their apical stereocilia and produce electromotile force along their lateral wall. Phase shifts, or time delays, in the transmembrane voltage occurring at different axial locations along the cell may contribute to our understanding of how these cells operate at auditory frequencies. We developed a method to optically measure the phase of the OHC transmembrane potential using the voltage-sensitive dye (VSD) di-8-ANEPPS. The exit aperture of a fibre-optic light source was driven in two dimensions so that a 24 microm spot of excitation light could be positioned along the length of the OHC. We used the whole-cell patch-clamp technique in the current-clamp mode to stimulate the OHC at the base. The photometric response and the voltage response were monitored with a photodetector and patch-clamp amplifier, respectively. The photometric response was used to measure the regional changes in the membrane potential in response to maintained (dc) and sinusoidal (ac) current stimuli applied at the base of the cell. We used a neutral density filter to lower the excitation light intensity and reduce phototoxicity. A sensitive detector and lock-in amplifier were used to measure the small ac VSD signal. This permitted measurements of the ac photometric response below the noise floor of the static fluorescence. The amplitude and phase components of the photometric response were recorded for stimuli up to 800 Hz. VSD data at 400-800 Hz show the presence of a small phase delay between the stimulus voltage at the base of the cell and the local membrane potential measured along the lateral wall. Results are consistent with the hypothesis that OHCs exhibit inhomogeneous membrane potentials that vary with position in analogy with the voltage in nerve axons.

Abstract

About 35% of patients with 22q11 deletion syndrome (22q11DS), which includes DiGeorge and velocardiofacial syndromes, develops psychiatric disorders, mainly schizophrenia and bipolar disorder. We previously reported that mice carrying a multigene deletion (Df1) that models 22q11DS have reduced prepulse inhibition (PPI), a behavioral abnormality and schizophrenia endophenotype. Impaired PPI is associated with several psychiatric disorders, including those that occur in 22q11DS, and recently, reduced PPI was reported in children with 22q11DS. Here, we have mapped PPI deficits in a panel of mouse mutants that carry deletions that partially overlap with Df1 and have defined a PPI critical region encompassing four genes. We then used single-gene mutants to identify the causative genes. We show that PPI deficits in Df1/+ mice are caused by haploinsufficiency of two genes, Tbx1 and Gnb1l. Mutation of either gene is sufficient to cause reduced PPI. Tbx1 is a transcription factor, the mutation of which is sufficient to cause most of the physical features of 22q11DS, but the gene had not been previously associated with the behavioral/psychiatric phenotype. A likely role for Tbx1 haploinsufficiency in psychiatric disease is further suggested by the identification of a family in which the phenotypic features of 22q11DS, including psychiatric disorders, segregate with an inactivating mutation of TBX1. One family member has Asperger syndrome, an autistic spectrum disorder that is associated with reduced PPI. Thus, Tbx1 and Gnb1l are strong candidates for psychiatric disease in 22q11DS patients and candidate susceptibility genes for psychiatric disease in the wider population.

Abstract

To determine the prevalence of radiographic empty sella in patients with spontaneous cerebrospinal fluid (CSF) otorrhea.Retrospective case series of adult patients with CSF otorhinorrhea at an academic tertiary medical center. Patients with history of skull base surgery, trauma, tumor, or chronic ear disease were excluded. Available imaging studies were reviewed with attention to the sella turcica.Eight patients were diagnosed with spontaneous CSF otorrhea. Five of seven patients with adequate imaging studies (71%) had a radiographic empty sella. Seven of eight patients were clinically obese, with a body mass index BMI>30 kg/m2.Empty sella is a common radiologic finding in patients with spontaneous CSF otorrhea. This supports the theory that increased intracranial pressure contributes to development of spontaneous CSF otorrhea.Radiographic empty sella predicts elevated intracranial pressure, which may require further evaluation and treatment in patients with spontaneous CSF otorrhea. EBM rating: C-4.

Abstract

To define the presentation of patients with skull base chondrosarcoma, to elucidate surgical strategies, and to identify the role of postoperative radiotherapy.Retrospective review.Tertiary referral center.All patients (n = 33) with skull base chondrosarcoma managed at our institution. The average follow-up time was 7.7 years (range, 0-20 years).Tumor location, presenting symptoms, presence of residual or recurrent tumor, and mortality.The most common tumor location was the petroclival junction (n = 29). Common presenting symptoms were diplopia (48%) and headache (45%). Surgical approaches included retrosigmoid, transtemporal, transfacial, and frontotemporal craniotomies. Biopsy only was performed in four patients, subtotal resection in 19 patients, and total resection in nine patients. Most patients received postoperative radiotherapy (82%). Follow-up revealed residual, stable disease in 28% of patients and recurrent disease in 24% of patients. The mean time to recurrence was 3.0 +/- 2.8 years. The lack of postoperative radiation was significantly correlated with an increased risk of recurrence (odds ratio, 28; p = 0.007) but incomplete tumor resection was not (p = 0.6). Life-table analysis revealed that the 5-year survival rate was 85% and the 10-year survival rate was 77%. Five patients died; four of the deaths attributable to recurrent disease.The characteristic growth pattern of skull base chondrosarcoma is tumor eroding the petroclival junction. Current therapeutic strategy is resection through an extradural subtemporal craniotomy with removal of the petrous apex and clivus. Radical resection of uninvolved structures is often not necessary. Nonetheless, gross total removal is often achievable. Postoperative radiotherapy reduces the chance of tumor recurrence.

Abstract

Cochlear outer hair cells change their length in response to variations in membrane potential. This capability, called electromotility, is believed to enable the sensitivity and frequency selectivity of the mammalian cochlea. Prestin is a transmembrane protein required for electromotility. Homozygous prestin knockout mice are profoundly hearing impaired. In humans, a single nucleotide change in SLC26A5, encoding prestin, has been reported in association with hearing loss. This DNA sequence variation, IVS2-2A>G, occurs in the exon 3 splice acceptor site and is expected to abolish splicing of exon 3.To further explore the relationship between hearing loss and the IVS2-2A>G transition, and assess allele frequency, genomic DNA from hearing impaired and control subjects was analyzed by DNA sequencing. SLC26A5 genomic DNA sequences from human, chimp, rat, mouse, zebrafish and fruit fly were aligned and compared for evolutionary conservation of the exon 3 splice acceptor site. Alternative splice acceptor sites within intron 2 of human SLC26A5 were sought using a splice site prediction program from the Berkeley Drosophila Genome Project.The IVS2-2A>G variant was found in a heterozygous state in 4 of 74 hearing impaired subjects of Hispanic, Caucasian or uncertain ethnicity and 4 of 150 Hispanic or Caucasian controls (p = 0.45). The IVS2-2A>G variant was not found in 106 subjects of Asian or African American descent. No homozygous subjects were identified (n = 330). Sequence alignment of SLC26A5 orthologs demonstrated that the A nucleotide at position IVS2-2 is invariant among several eukaryotic species. Sequence analysis also revealed five potential alternative splice acceptor sites in intron 2 of human SLC26A5.These data suggest that the IVS2-2A>G variant may not occur more frequently in hearing impaired subjects than in controls. The identification of five potential alternative splice acceptor sites in intron 2 of human SLC26A5 suggests a potential mechanism by which expression of prestin might be maintained in cells carrying the SLC26A5 IVS2-2A>G DNA sequence variation. Additional studies are needed to evaluate the effect of the IVS2-2A>G transition on splicing of SLC26A5 transcripts and characterize the hearing status of individuals homozygous for the IVS2-2A>G variant.

Abstract

Intracochlear scarring is a well-described sequela of cochlear implantation. We developed a mathematical model of passive cochlear mechanics to predict the impact that this might have upon residual acoustical hearing after implantation. The cochlea was modeled using lumped impedance terms for scala vestibuli (SV), scala tympani (ST), and the cochlear partition (CP). The damping of ST and CP was increased in the basal one half of the cochlea to simulate the effect of scar tissue. We found that increasing the damping of the ST predominantly reduced basilar membrane vibrations in the apex of the cochlea while increasing the damping of the CP predominantly reduced basilar membrane vibrations in the base of the cochlea. As long as intracochlear scarring continues to occur with cochlear implantation, there will be limitations on hearing preservation. Newer surgical techniques and electrode technologies that do not result in as much scar tissue formation will permit improved hearing preservation.

Abstract

Although mastoid and middle ear obliteration provides the ultimate repair of an encephalocele, retained squamous epithelium may result in the occult recurrence of cholesteatoma. For most patients, a preferable technique is to perform a canal-wall-up mastoidectomy with middle fossa craniotomy. However, temporal lobe encephaloceles are occasionally found in patients with canal-wall-down cavities along with active cholesteatoma. We sought to describe our management strategy for this dilemma.Retrospective review.Tertiary referral center.We reviewed all patients with encephaloceles treated by the primary surgeon. Patients without active cholesteatoma and a canal-wall-down cavity were excluded.Surgical management of the encephalocele and cholesteatoma.Successful repair and a noninfected ear.Three patients met the inclusion criteria. All had previous canal-wall-down surgery for cholesteatoma by outside surgeons and presented with chronic otorrhea, large tegmen defects, and brain herniation into the mastoid cavity. All had incomplete removal of their posterior canal wall. Our management strategy involved completing the canal-wall-down mastoidectomy and repairing the temporal floor defect using a three-layer closure via a middle fossa craniotomy. This included suture repair of the dural defect with or without a graft, a temporalis muscle rotation flap, and a split-calvarial bone graft. All patients recovered from their surgery without evidence of further cerebrospinal fluid leak, encephalocele, or cholesteatoma with a minimum follow-up time of 6 months.A temporal lobe encephalocele can be safely repaired while maintaining a mastoid bowl. This may be the safest treatment option for patients with active cholesteatoma.

Abstract

Superior canal dehiscence syndrome is a recently described condition resulting in noise- or pressure-induced vertigo. We review the case of a 50-year-old woman who presented with debilitating pressure and noise-induced vertigo as well as a low-frequency conductive hearing loss. Imaging was consistent with superior semicircular canal dehiscence syndrome. An extradural middle fossa approach was used to approach the dehiscent superior canal. Intraoperatively, our patient was found to have extensive idiopathic skull base dehiscence of the temporal floor. Middle ear and mastoid mucosa was exposed with focal areas of dura prolapsed into the mastoid cavity. Because of these findings, temporalis fascia and bone pate were used to cover the dehiscent canal as well as a large area of the temporal floor. Additionally, a temporalis muscle flap was rotated between the dura and the dehiscent temporal floor to reconstruct the middle fossa skull base and prevent encephalocele.

Abstract

Outer hair cell (OHC) electromotility provides mechanical positive feedback that functions as the cochlear amplifier. In isolated OHCs, chlorpromazine shifts the electromotility voltage-displacement transfer function in a depolarizing direction without affecting its magnitude. This study sought to measure the effects of chlorpromazine on cochlear function in vivo. Salicylate, a drug that greatly reduces the magnitude of electromotility, was used for comparison. Perilymphatic perfusion of the guinea pig cochlea with chlorpromazine or salicylate increased the compound action potential (CAP) threshold across the frequency spectrum (1-20 kHz). Both drugs also increased distortion product otoacoustic emission (DPOAE) thresholds in the higher frequencies (10-20 kHz). Complete reversibility of these effects occurred after washout. Both drugs demonstrated concentration-dependent reductions in cochlear function that followed sigmoidal curves with similar fits to previously reported results in isolated OHCs. The endolymphatic potential was not affected by either of these drugs. Thus, chlorpromazine inhibits cochlear function in a manner consistent with what would be expected from data in isolated OHCs. This suggests that shifting the electromotility transfer function correspondingly reduces the gain of the cochlear amplifier.

The cochlear amplifier: augmentation of the traveling wave within the inner ear.Current opinion in otolaryngology & head and neck surgeryOghalai, J. S.2004; 12 (5): 431-438

Abstract

There have been many recent advancements in our understanding of cochlear function within the past ten years. In particular, several mechanisms that underlie the sensitivity and sharpness of mammalian tuning have been discovered. This review focuses on these issues.The cochlear amplifier is essentially a positive feedback loop within the cochlea that amplifies the traveling wave. Thus, vibrations within the organ of Corti are sensed and then force is generated in synchrony to increase the vibrations. Mechanisms that generate force within the cochlea include outer hair cell electromotility and stereociliary active bundle movements. These processes can be modulated by the intracellular ionic composition, the lipid constituents of the outer hair cell plasma membrane, and the structure of the outer hair cell cytoskeleton.A thorough understanding of the cochlear amplifier has tremendous implications to improve human hearing. Sensorineural hearing loss is a common clinical problem and a common site of initial pathology is the outer hair cell. Loss of outer hair cells causes loss of the cochlear amplifier, resulting in progressive sensorineural hearing loss.

Abstract

To elucidate indications and outcomes with the transjugular craniotomy for resection of jugular foramen tumors with intracranial extension. The transjugular approach is a lateral craniotomy conducted through a partial petrosectomy traversing the jugular fossa combined with resection of the sigmoid sinus and jugular bulb, which often have been occluded by disease.Retrospective review.University medical center.Twenty-eight patients with intracranial jugular foramen tumors who underwent a total of 30 surgical procedures.Pathologic findings, surgical approach, extent of tumor resection, rate of facial nerve mobilization and ear canal closure, facial and lower cranial nerve outcomes, and hearing preservation.Tumors included schwannoma (37%), meningioma (33%), glomus jugulare (23%), and chordoma (7%). The surgical approaches were tailored to maximize functional preservation, and included the transjugular (53%), translabyrinthine (17%), retrosigmoid (10%), and far lateral (7%) craniotomies. Translabyrinthine (3%) or transcondylarfar lateral (3%) approaches were occasionally used in combination with the trans-jugular approach. Most procedures were managed in a single stage (90%), but three patients with massive tumor in the neck required two stages. Microsurgical gross total and near-total tumor removal (37% each) were commonly achieved, although subtotal resections (27%) were occasionally performed. In only a minority of cases was facial nerve mobilization (7%) or ear canal closure (21%) required. If present preoperatively, Grade I facial nerve function was usually maintained (22 of 24 [92%]) and Hearing Class A or B could always be maintained (9 of 9 [100%]). As expected, new lower cranial nerve dysfunction was common (8 of 30 [27%]), although over half of the patients had complete lower nerve palsy preoperatively (16 of 30 [53%]).Most patients with jugular foramen tumors with intracranial extension can be managed with a single-stage transjugular craniotomy. Facial nerve mobilization or ear canal closure is usually not required, permitting conservation of facial function and hearing, when present preoperatively.

Abstract

The objective of this study was to characterize the auditory dysfunction associated with chronic pachymeningitis (inflammation of the dura mater).We conducted a university-based retrospective review.Three patients were identified who were diagnosed with chronic pachymeningitis after being referred for asymmetric sensorineural hearing loss. All patients were found to have other neurologic symptoms and signs during careful neurotologic evaluation. Two varieties of chronic pachymeningitis exist: a hypertrophic mass lesion and a linear dural thickening. Although the hypertrophic variety could be easily detectable by noncontrast magnetic resonance imaging (MRI), the linear form is only visible with the use of gadolinium enhancement.Chronic pachymeningitis is a rare form of sensorineural hearing loss that could portend an underlying disease of greater concern. Extensive evaluation is needed to exclude identifiable causes of chronic pachymeningitis, including infectious, neoplastic, and autoimmune diseases.The clinician should be aware that the evaluation of a patient with asymmetric sensorineural hearing loss involves more than simply ruling out an acoustic neuroma. Fast-spin echo MRI techniques without the use of gadolinium contrast could miss a number of potentially treatable diseases such as chronic pachymeningitis. Patients with asymmetric sensorineural hearing loss should be carefully evaluated for other neurologic findings, and imaging with enhanced MRI is recommended.

Abstract

We sought to determine the recurrence rate after near-total and subtotal resection of acoustic neuroma. STUDY DESIGN, SETTING, AND PATIENTS: We conducted a retrospective chart review of a total of 79 patients: 50 with near-total resections (remnant < or =25 mm(2) and < or =2 mm thick) and 29 with subtotal resections (any larger remnant). Surgical approach included 5 middle fossa, 17 retrosigmoid, and 57 translabyrinthine.Recurrence was defined as documented tumor growth by serial imaging or the recommendation for further treatment after a single scan. No recurrence was defined as no visible tumor on imaging for a minimum follow-up time of 3 years or tumor remnants that remained unchanged on serial scans (mean, 5-year follow-up).Fifty-two patients were included in the study group. Recurrences were seen in 1 (3%) of 33 patients who had a near-total resection compared with 6 (32%) of 19 patients who had a subtotal resection. After adjustment for follow-up time and large tumor size, the odds ratio for recurrence was 12 times larger for subtotal than for near-total resections (P = 0.033). All recurrences were seen following the translabyrinthine approach in the mid-cerebellopontine angle. None were encountered in the internal auditory canal. The mean time interval from surgery to the detection of a recurrence was 3 years (range, 1 to 5 years).The recurrence rate when performing a near-total resection is low but is substantially higher with a subtotal resection. Recurrences can be detected within the first 5 postoperative years. We recommend near-total resection in any patient if needed to preserve neural integrity. Subtotal resection is best avoided whenever possible; however, adjunctive treatment with stereotactic radiotherapy may be considered.

Abstract

The cochlea is the part of the inner ear that transduces sound waves into neural signals. The basilar membrane, a connective tissue sheet within the cochlea, is tonotopically tuned based on the spatial variation of its mass, stiffness, and damping. These biophysical properties are mainly defined by its constituent collagen fibers. We sought to assess the effect of laser irradiation on collagen within the basilar membrane using histological analysis.Four excised guinea pig cochleae were stained with trypan blue. From these, two were irradiated with a 600 nm pulsed dye laser and two were used as controls. Collagen organization was visualized using polarization microscopy.Laser irradiation reduced the birefringence within the basilar membrane as well as within other stained collagen-containing structures. Larger reductions in birefringence were measured when more laser pulses were given. The effects were similar across all turns of each cochlea.Laser irradiation causes immediate alterations in collagen organization within the cochlea that can be visualized with polarization microscopy. These alterations may affect cochlear tuning. Ongoing research is aimed at analyzing the effect of laser irradiation on cochlear function. It is conceivable that this technique may have therapeutic benefits for patients with high-frequency sensorineural hearing loss.

Abstract

The goal of combined retrolabyrinthine-middle fossa craniotomy is to provide exposure of both the middle and posterior cranial fossae via a partial petrosectomy and division of the tentorium. Its major benefits over others are that hearing and facial nerve function are preserved and only minimal brain retraction is required. The retrolabyrinthine approach involves a presigmoid posterior fossa craniotomy that preserves the structures of the inner ear. Additionally, a middle fossa craniotomy, extending to the zygomatic root, is performed to gain access to the superior aspect of the temporal bone in the middle cranial fossa. This approach works well in cases of lesions involving the petroclival junction, including petroclival meningiomas, trigeminal schwannomas, epidermoids, and large chondrosarcomas or chordomas with intradural components. The authors describe the surgical technique of this approach.

Abstract

To determine the hearing outcome in patients undergoing surgery via the retrosigmoid approach for acoustic neuromas with a substantial component in the cerebellopontine angle.Retrospective case review.Tertiary referral center.The medical records of all patients undergoing acoustic neuroma removal via the retrosigmoid approach at a tertiary referral center were retrospectively reviewed. Sixty-four patients with both cerebellopontine angle component >or=15 mm and preoperative audiometry of class A or B (American Academy of Otolaryngology-Head and Neck Surgery) were identified.Postoperative average pure tone threshold and word recognition scores, categorized according to the classification of the American Academy of Otolaryngology-Head and Neck Surgery, were used to assess hearing outcome.Overall, only 6.3% (4 of 63) retained good hearing (class A or B) postoperatively. Hearing preservation rate in the smallest (15- to 19-mm) group was 17.6% (3 of 17), which was better than that for the larger groups. No successful hearing preservation was achieved in tumors with >or=25 mm cerebellopontine angle component (0 of 23).Surgeon and patient alike would always choose a hearing preservation technique if there was no potential for increased morbidity in making the attempt. When compared with the non-hearing preservation translabyrinthine approach, the retrosigmoid approach had a higher incidence of persistent headache. In addition, efforts to conserve the auditory nerve prolong operating time, increase the incidence of postoperative vestibular dysfunction, and carry a slightly higher risk of tumor recurrence. Nevertheless, even though the probability of success is disappointingly small, when excellent hearing is present we favor offering the option of a hearing conservation attempt when the patient has been well informed of the pros and cons of the endeavor. Factors weighing against undertaking this effort include larger cerebellopontine angle component (>or=25 mm), deep involvement of the fundus, wide erosion of the porus, and marginal residual hearing.

Abstract

To ascertain the effect of age on hearing preservation, facial nerve outcome, and complication rates after acoustic neuroma surgery.Retrospective chart review. Two study arms were used: a comparison of the authors' oldest patients with their youngest patients (extremes of age arm) and an analysis of all middle fossa surgical procedures (middle fossa arm).Tertiary referral centerTotal of 329 patients. For the extremes of age arm, 205 patients were studied in two cohorts with 150 older patients (>60 years) compared with 55 younger patients (<40 years). The approaches included 21 middle fossa (MF), 38 retrosigmoid (RS), and 91 translabyrinthine (TL) procedures in the older group versus 25 MF, 17 RS, and 13 TL in the younger. For the middle fossa arm, there were 170 patients (age range 15-76 years) who underwent the MF approach for an attempt at hearing preservation.Hearing preservation was defined as the maintenance of either class A or class B hearing (AAO-HNS class). Good facial nerve outcome was considered the maintenance of either grade 1 or 2 (House-Brackmann scale). Cerebrospinal fluid leak rates and other postoperative complications were also tabulated.After adjustment for tumor size and surgical approach using multiple logistic regression analysis, the extremes of age study arm demonstrated that there is a lower chance of preserving good hearing in older patients (p = 0.048, odds ratio = 0.30). Age was not associated with a difference in the rate of good facial nerve outcome (p = 0.2). There was a trend toward slightly higher rates of cerebrospinal fluid leak in the older patient group (p = 0.07) but no difference in the rate of other complications (p = 0.9). The middle fossa study arm, after adjustment for tumor size and surgical approach, demonstrated that older patient age is associated with a lower rate of preservation of good hearing (p = 0.01, O.R.=1.044). There was no association between age and good facial outcome (p = 0.7).Older patient age lowers the chance of hearing preservation but does not affect facial outcomes. There is a trend toward a higher rate of cerebrospinal fluid leak in older patients, but no increased risk of other complications.

Abstract

To evaluate hearing preservation and facial nerve (FN) outcome in the middle fossa (MF) approach for acoustic neuromas with a cerebellopontine angle (CPA) component >10 mm.Retrospective review of 193 patients.Patients were grouped according to tumor size: intracanalicular tumors (IC; 64), 1 to 9 mm CPA extension (42), and 10 to 18 mm CPA extension (47). Additionally, a group of 40 patients (tumor size 10-18 mm CPA extension) who had undergone a translabyrinthine (TL) approach was studied to assess comparative FN outcome. Hearing and FN function were measured 1 year postoperatively. We defined the success at functional hearing preservation as AAO-HNS class B or better and good FN outcome as House-Brackmann grade II or better.For IC tumors and those with up to 9-mm CPA extension, there was no significant difference in the rate of functional hearing preservation (62.2% vs. 63.1%, P =.931) and good FN outcome (93.7% vs. 97.6%, P =.358). For tumors of 10- to 18-mm CPA extension, the rate of hearing preservation (34%) was lower than the other groups (P =.006 and P =.009). In this group, the rate of good FN outcome was lower compared with the IC and 1- to 9-mm tumors (80.8% vs. 93.7%, P =.037 and 97.6%, P =.012). The rate of good FN outcome following the TL approach in a comparable cohort of patients was 100% (P =.003 in comparison with 10-18 mm tumor resected with the MF approach).When considering surgical options, patients with >10-mm tumors should be advised that choosing the MF approach for hearing preservation carries a somewhat higher risk of persistent FN dysfunction.

Abstract

To compare the risk factor profile for neonatal hearing loss (HL), and the follow-up rate of those identified with HL in an indigent population with those in an insured population.Retrospective review.We studied 4526 neonates from the high-risk nursery or neonatal intensive care unit from two adjacent hospitals in Houston, Texas. Ben Taub General Hospital (BTGH) is a county public hospital that serves mainly the indigent. Texas Children's Hospital (TCH) is a private tertiary care center that serves patients with private insurance and Medicaid.Overall, 133 infants failed the screening test. Follow-up diagnostic testing identified 48 patients with definite HL. Although nearly twice as many patients at BTGH failed screening compared with TCH (88 vs. 45), four times as many patients at BTGH did not return for diagnostic testing (43 vs. 10). When a hearing aid was needed, there was a delay in getting one at BTGH (P .1).Significant differences in the risk factor profile for neonatal HL exist between the indigent and the general population. A worrisome problem exists with the timely intervention in hearing-impaired indigent neonates.

Abstract

Balance disorders in elderly patients are associated with an increased risk of falls but are often difficult to diagnose because of comorbid chronic medical problems. We performed a cross-sectional study to determine the prevalence of unrecognized benign paroxysmal positional vertigo (BPPV) and associated lifestyle sequelae in a public, inner-city geriatric population. Dizziness was found in 61% of patients, whereas balance disorders were found in 77% of patients. Nine percent were found to have unrecognized BPPV. Multivariate analysis demonstrated that the presence of a spinning sensation and the absence of a lightheadedness sensation predicted the presence of unrecognized BPPV. Patients with unrecognized BPPV were more likely to have reduced activities of daily living scores, to have sustained a fall in the previous 3 months, and to have depression. These data indicate that unrecognized BPPV is common within the elderly population and has associated morbidity. Further prospective studies are warranted.

Abstract

The mechanism responsible for electromotility of outer hair cells in the ear is unknown but is thought to reside within the plasma membrane. Lipid lateral diffusion in the outer hair cell plasma membrane is a sigmoidal function of transmembrane potential and bathing media osmolality. Cell depolarization or hyposmotic challenge shorten the cell and reduce membrane fluidity by half. Changing the membrane tension with amphipathic drugs results in similar reductions. These dynamic changes in membrane fluidity represent the modulation of membrane tension by lipid-protein interactions. The voltage dependence may be associated with the force-generating motors that contribute to the exquisite sensitivity of mammalian hearing.

Abstract

The sensory hair cells of the inner ear are responsible for converting balance and hearing stimuli into electrical signals. Until recently, all previous studies of hair cell physiology had been performed on tissue obtained from non-mammals and rodents. In primates, hair cells are difficult to access, because they rest within the densest structure of the body, the otic capsule of the temporal bone. In this report, we describe a technique that we have used in physiological studies to harvest living human hair cells. We collected vestibular and cochlear tissue specimens from adult humans undergoing translabyrinthine and transotic surgical approaches for resection of lateral skull base tumors. Viable hair cells were identified and visualized with light microscopy. The ability to study normal hair cells from humans may further the study of normal and pathological human sensation, hair cell regeneration, and genetic causes of balance and hearing disorders.

Abstract

Cochlear outer hair cell (OHC) electromotility is associated with the cell's lateral wall. The lateral wall contains two distinct membranes: the plasma membrane (PM) and the subsurface cisternae (SSC). We explored biophysical characteristics of these lipid structures using membrane-specific fluorescent dyes. We have previously demonstrated that di-8-ANEPPS stains the PM while NBD-C6-ceramide partitions to the SSC. In this report we show that NBD-cholesterol also partitions to the SSC. Transmigration of the SSC dyes across the PM was visualized under confocal microscopy, after separating the two membranes using the micropipette aspiration technique. The transverse mobility of NBD-cholesterol was faster than that of NBD-C6-ceramide. We then measured the lateral mobility of the dyes within both the PM and the SSC using fluorescence recovery after photobleaching (FRAP). The diffusion coefficients at 12 37 degrees C and the activation energies for diffusion were found to be similar to those of other biological membranes. These data indicate that both the PM and the SSC are membranes in the fluid phase, with no evidence of temperature-dependent phase transitions. Our observations are consistent with a fluid-mosaic model of the lateral wall membranes.

Abstract

The upright posture and rich vocalizations of primates place demands on their senses of balance and hearing that differ from those of other animals. There is a wealth of behavioral, psychophysical, and CNS measures characterizing these senses in primates, but no prior recordings from their inner ear sensory receptor cells. We harvested human hair cells from patients undergoing surgical removal of life-threatening brain stem tumors and measured their ionic currents and electromotile responses. The hair cells were either isolated or left in situ in their sensory epithelium and investigated using the tight-seal, whole cell technique. We recorded from both type I and type II vestibular hair cells under voltage clamp and found four voltage-dependent currents, each of which has been reported in hair cells of other animals. Cochlear outer hair cells demonstrated electromotility in response to voltage steps like that seen in rodent animal models. Our results reveal many qualitative similarities to hair cells obtained from other animals and justify continued investigations to explore quantitative differences that may be associated with normal or pathological human sensation.

Abstract

Outer hair cell (OHC) electromotility appears to be central to mammalian hearing and originates within its lateral wall. The OHC lateral wall is a unique trilaminate structure consisting of the plasma membrane (PM), the cortical lattice (CL), and the subsurface cisternae (SSC). We selectively labeled and imaged the lateral wall components in the isolated guinea pig OHC under confocal microscopy. The PM was labeled with a voltage-sensitive dye, di-8-ANEPPS; the SSC was labeled with the sphingomyelin precursor, NBD-C6-ceramide; and F-actin in the CL was labeled with conjugates of phalloidin. Interactions among the three layers were evaluated with the micropipette aspiration technique. The PM was tethered to the CL and SSC until, at a critical deformation pressure, the PM separated, allowing visualization of the extracisternal space, and ultimately formed a vesicle. After detaching, the stiffness parameter of the PM was 22% of that of the intact lateral wall. We conclude that the lateral wall PM is more compliant than the CL/SSC complex. The data clarify the structural basis for electromotile force coupling in the OHC lateral wall.

Abstract

A software routine to reconstruct individual spike trains from multi-neuron, single-channel extracellular recordings was designed. Using a neural network algorithm that automatically clusters and sorts the spikes, the only user input needed is the threshold level for spike detection and the number of unit types present in the recording. Adaptive features are included in the algorithm to allow for tracking of spike trains during periods of amplitude variation and also to identify noise spikes. The routine will operate on-line during extracellular studies of the cochlear nucleus in cats.